The disease is a group of autosomal recessive congenital disorders in which both parents are heterozygous and the patient is purely heterozygous, and is more common in children of consanguineous parents. Cortisol synthesis is partially or completely blocked due to defects in enzymes related to adrenocortical hormone synthesis, resulting in increased CRH-ACTH secretion from the hypothalamus-pituitary gland, leading to adrenocortical hyperplasia. Since these enzymes are required for adrenal and gonadal steroid synthesis, the enzyme deficiency causes both adrenal and gonadal steroid synthesis impairment, with increased pre-blockade intermediate compounds and decreased post-blockade steroid hormones. The known types of congenital adrenocortical hyperplasia are P450c21 (21-hydroxylase), P450cl1 (11-β hydroxylase), P450c17 (17α-hydroxylase, 17,20 lyase), 3β steroid dehydrogenase, and P450scc (20,22 charcoal chain enzyme and 20,22 hydroxylase deficiency). Different types of enzyme deficiencies produce different biochemical changes and clinical manifestations. Early diagnosis and treatment are very important, especially for P450c21 and P450c11 deficiencies, which, if diagnosed and treated from early embryonic stages, can prevent the emergence of androgenesis and result in normally developing infants, but failure to recognize them at birth often leads to later abnormal development and, in severe cases, premature death in infancy.
The 21-hydroxylase deficiency type is the most common type of congenital adrenocortical hyperplasia, accounting for 90% to 95% of the total.
Clinical classification
Severe (salt loss type), medium (simple masculinization type), and mild (late type).
The enzyme deficiency is partial, so blood cortisol can be normal or nearly normal under high concentration of ACTH excitation, and there is no adrenocortical insufficiency at birth, but there is hyperpigmentation of the skin due to ACTH. Also due to the accumulation of cortisol precursor compounds, especially androgen increase, resulting in female clitoral hypertrophy, female pseudohermaphroditism; male precocious puberty.
2, salt loss type; masculinization with salt loss accounts for more than 1/3 of this syndrome, due to the complete lack of P450c21, despite the high concentration of ACTH, blood cortisol is still lower than normal, and the precursor compounds progesterone and 17-hydroxyprogesterone increase, these hormones have a clear tendency to excrete sodium, coupled with the serious lack of this enzyme, aldosterone synthesis is blocked at the same time, sodium deficiency is more serious. Infants often show acute adrenocortical insufficiency 5 to 15 days after birth, which eventually leads to sodium loss and dehydration leading to circulatory failure, and death may occur due to hyperkalemic cardiac arrest. The androgen secretion of this type is higher than that of the purely masculine type, so female infants have more complete androgenization of the external genitalia, with penis and complete urethra, and the labia majora are completely fused like the scrotum, but the testes cannot be retrieved, and suspected cases can be identified only by chromosomal analysis and blood and urine hormone determination.
3.Late onset (or adult onset): Only seen in females. Because there is only a very small amount of androgen in the embryonic period, which is not enough to make the female external genitalia androgenic, so the female infant is completely normal at birth, and there is no obvious feminization after birth. There may be normal pubertal development, but after childbirth, hirsutism and menstrual disorders may occur, as well as secondary amenorrhea, infertility and polycystic ovaries. The main diagnostic method is ACTH excitation test, and 17-hydroxyprogesterone can be diagnosed by a significant increase.
Clinical manifestations
1. Hypoadrenocorticism symptoms: different degrees of anorexia, nausea, vomiting, hypoglycemia and other symptoms may occur depending on the degree of enzyme deficiency, and in severe cases, hyponatremia, hyperkalemia and metabolic acidosis. Due to the increase of ACTH, there are different degrees of hyperpigmentation, similar to the performance of Addison’s disease, the whole body skin black, skin folds, such as finger joint extension, armpits, groin, areola around especially obvious. Blood pressure is generally normal, but in heavy cases, circulatory failure.
2. Abnormal development of sexual differentiation: females show masculinization, males show precocious sexual maturity. The masculine change of female external genitalia is called “female pseudohermaphroditism”, with enlarged clitoris, frequent erection, high sexual desire, and easy masturbation habit. The internal genitalia are still female, and there may be primary or secondary amenorrhea, infertility, and polycystic ovaries. In males, the development of external genitalia accelerates 1 to 2 years after birth, and the penis and prostate gland are as large as puberty at the age of 3 to 4 years, often showing excessive development, which is called “precocious genital giant malformation”, and in untreated adult males, the function of interstitial cells and sperm production are mostly normal, and a few patients do not have normal puberty, small testicular size, no spermatozoa, and sterility. Females have pubic and axillary hair at the age of 2 to 3 years, and by puberty have thick laryngeal nodes, low tone, no breast development, and increased body hair, similar to males. Males have pubic and axillary hair growth, increased body hair, and acne at the age of 3 to 4 years. In early childhood, growth is accelerated, muscles are developed, shoulders are wide, skin is rough and taller than peers, and the epiphysis is fused early due to the action of androgens (completely fused at the age of 11 to 12), and finally height is lower than peers, body shape is short and ugly, and finally grows into a small “Hercules” body type with short and broad shoulders.
3. Other manifestations: personality change, hyperactivity, inattention, poor academic performance, which may be related to excessive androgens.
Laboratory tests and imaging examinations
1. Urinary 17-ketosteroid (17-KS) is an important test, which can be as high as 30~50mg/24h, significantly higher than the level of normal adults. True precocious puberty and true hermaphroditism are in the normal range.
2.Dexamethasone inhibition test: Dexamethasone 2mg, divided into oral doses for 7 days, urinary 17-ketones were inhibited to normal levels, while adrenal androgenic tumors could not be inhibited.
3. Urinary pregnanetriol increased significantly, and pregnanediol also increased to varying degrees, but the increase of pregnanetriol in newborn infants was not obvious because of the low glucuronide conversion enzyme activity in newborns, and the clinical measurement was mainly the glucuronide-binding fraction.
4, plasma 17-hydroxyprogesterone, androstenedione, testosterone increase, adult female testosterone can approach the male level of 6, 93nmol/L (about 400ng/dl), 24h after birth, plasma progesterone > 63, 6nmol/L (2000ng/d1) (normal infants 24h after birth, blood progesterone decline to normal levels), but should pay attention to preterm infants, stress state However, it should be noted that 17-hydroxyprogesterone may remain elevated in preterm and full-term fetuses under stress.
5.Blood cortisol and urinary 17-hydroxycorticosteroid are lower than normal for the salt loss type, and within the normal range for the simple masculinization type. The response to ACTH excitation test is lower than normal, indicating insufficient reserve function.
6.Adrenomedullary hormone is normal or decreased. In the process of adrenomedullary hormone synthesis, the transformation of norepinephrine (NE) into epinephrine (E) requires PNMT (phenylethanolamine-N-methyltransferase) catalysis, and the activity of this enzyme depends on high concentration of cortisol induction, so the less cortisol is produced, the lower the PNMT is, which finally leads to less E synthesis. Thus, the level of adrenal medulla can indirectly respond to the severity of 21-hydroxylase deficiency.
7.Blood electrolytes: low sodium, high potassium acidosis, and low blood sugar, suggesting adrenocortical insufficiency.
8.Plasma renin activity is increased, and blood aldosterone is low or normal.
9.Karyotype analysis: determine the hereditary sex of hermaphroditism.
10.Intravenous pyelogram and genital tract imaging can show the differentiation status of urogenital sinus and the presence of urethral malformation.
Ultrasound or CT of the adrenal glands: both the salt-losing type and the purely masculine type show a marked enlargement of the adrenal glands, with equilateral triangular or circular changes that are mistaken for tumors. It can be 4 to 10 times larger than normal, and single or multiple nodule formation can be seen in older cases.
Diagnosis and differential diagnosis
In clinically suspicious cases, glucocorticoid treatment can effectively improve clinical symptoms is the most important diagnostic basis, and it is also the only measure that the salt loss type can survive, but some selective tests must be done in order to confirm the diagnosis.
Female congenital adrenocortical hyperplasia simple masculine type should be differentiated from the following sex characteristics abnormalities: 1 male pseudohermaphroditism (XY) and XO/XY chimerism, although the external genitalia have similar manifestations, but the karyotype of patients with this disease simple masculine type is XX. 2 true hermaphroditism, the external genitalia are similar, the karyotype can be XX, but the blood androgens and urinary 17-ketones are normal. 3 non-adrenal source androgens In addition to female pseudohermaphroditism of unknown origin, there are also female pseudohermaphroditism with urogenital tract anomalies such as double ureter, vesico-enteric fistula, congenital anal atresia, and other anomalies.4 Late onset disease must also be differentiated from polycystic ovaries. In male children, the disease should be differentiated from childhood androgenic tumors and early appearance of pubic hair.
Treatment of 21-hydroxylase defects
1. Diagnostic treatment during embryonic period: amniocentesis to measure 17-hydroxyprogesterone and Δ4 androstenedione in amniotic fluid, and if they are increased, the disease can be diagnosed. If the fetus is diagnosed as female congenital adrenocortical hyperplasia, treatment can be started at 3-10 weeks (preferably before 6 weeks), generally with dexamethasone easily passing through the placenta at a dose of 20μg/kg daily (1~1,5mg/24h), divided into 2-3 oral doses until the end of pregnancy. This dose can effectively inhibit the fetal pituitary ACTH overproduction, thus preventing fetal androgenesis, preventing labia majora fusion and clitoral hypertrophy, and no adverse effects on the fetus have been found so far, and there are no malformations or other risks.
2. Postnatal treatment: Treatment should be continued after birth, with the aim of correcting acute adrenocortical insufficiency in newborns, suppressing excessive ACTH, reducing intermediate metabolites such as 17-hydroxyprogesterone and 21-desoxycortisol, and then reducing androgens, preventing androgenization, slowing down growth rate, bringing epiphyseal fusion closer to normal age, achieving normal height as much as possible, and restoring normal ovulation and fertility. The aim of treatment for male patients is to stop pseudo-precocious puberty and restore fertility.
3. Treatment principles.
①Start treatment as early as possible.
②Cortisol or corticosteroid is the drug of choice; prednisone and prednisolone can be used, but the effect of sodium retention is weak; dexamethasone is not suitable for application in childhood, but can be applied in adults.
③The size of the maintenance dose varies from person to person.
④The importance of treatment should be emphasized to parents. Women must be treated for life, and the dose of treatment should be increased in case of stress, otherwise it can lead to fatal adrenocortical insufficiency crisis.
4. Classical method (alternative suppressive therapy): Larger doses of cortisone acetate can be used at the beginning. After a week, the adrenal glands reach maximum suppression, urinary 17-ketone and progesterone excretion drop to normal, then switch to hydrocorticotropin to maintenance amount, or can be given maintenance amount at the beginning, but it takes a long time to obtain complete suppression.
5. Application of salt corticosteroids: 9α fluorohydrocortisone sodium retention is 400 times more potent than hydrocortisone, and can be used as aldosterone replacement therapy at a dose of 0.05-0.1 mg/24h, orally. Hydrocortisone combined with 9α fludrocortisone is the most effective treatment option. The best hormonal indicators for control of 21-hydroxylase are blood 17-hydroxyprogesterone and Δ4 androstenedione. Dose adjustment in combination with plasma renin activity, steroid hormone intermediate metabolites (and blood ACTH if available), growth curve, bone age, and pubertal development is generally successful. Female patients need lifelong replacement therapy, otherwise it may cause secondary amenorrhea and androgenic symptoms. Males (simple masculinization type) can interrupt treatment until adulthood when they have sufficient height, while heavy (salt loss type) should have lifelong replacement therapy regardless of male or female.
Management of acute hyperalgesia crisis: acute hyperalgesia often occurs 3-15 days after birth in the salt-losing type: anorexia, severe nausea, vomiting, acidosis, and circulatory failure. If not diagnosed and treated in time often leads to premature death. When the diagnosis is suspicious, urine and blood should be collected immediately to further clarify the diagnosis, while correcting dehydration (the first hour to 5% glucose saline 20ml/kg + hydrocortisone 20mg, iVgtt), if there is improvement, continue rehydration (dose of 5% glucose saline 60ml/kg per day), if there is acidosis, with 1/6 mol sodium lactate added to the rehydration solution drip. If no improvement is seen after the first hour, sodium retention hormone DOCA 1-2mg, bid, im or 9α fludrocortisone 0, 1mg, po should be given and changed to maintenance dose when the symptoms improve.
6. Other treatments: glucocorticoid extended-release preparations, ACTH-releasing hormone (CRH) antagonists, anti-androgen drugs and aromatase inhibitors, drugs that block the production of adrenal-derived androgens, luteinizing hormone-releasing hormone (LHRH) analogs and growth hormone (GH) therapy, and gene therapy are under further investigation.
11 β-hydroxylase deficiency type
Clinical manifestations]: This type is rare and accounts for about 3% of congenital adrenocortical hyperplasia. This type is also divided into heavy and late forms. Due to overproduction of deoxycorticosterone (DOC), most patients have mild hypertension, while a few have severe hypertension and hypokalemia. After cortisone replacement therapy, hypertension and hypokalemia may return to normal. A few patients are known to have no hypertension, and it is assumed that this enzyme defect is partial, with an insignificant increase in DOC offset by a decrease in aldosterone secretion. These patients are easily confused clinically with the purely masculine form of 21-hydroxylase deficiency. Occasionally, some newborns have mild salt loss, with a gradual increase in DOC with age, resulting in hypertension and hypokalemia. Female patients are born with androgenesis of the external genitalia similar to 21-hydroxylase deficiency, but to a lesser extent than the latter. Late onset patients tend to develop at puberty and present with hypertrichosis, acne, menstrual disorders, infertility, clitoral hypertrophy (without labia majora fusion), hypertension may or may not be present, male children are often difficult to identify, the only diagnostic clues are rapid growth and early appearance of pubic hair.
The only diagnostic clues are rapid growth and early appearance of pubic hair. [Diagnosis and Differential Diagnosis]: In addition to androgenicity, there is a characteristic increase in deoxycortisol in the blood, so urinary 17-OHCS shows an increase. Urinary 17-KS and pregnanetriol can be suppressed by dexamethasone also helps in the diagnosis and can be differentiated from adrenal androgenic tumors, which cannot be suppressed by dexamethasone.
Treatment】: The drug of choice is dexamethasone, because the hormone not only has no sodium retention effect, but also has a mild sodium-removal effect. Dexamethasone 0,75mg, q8h, po was used at the beginning to suppress excessive ACTH secretion, so that the intermediate metabolites dropped to normal, and androgens also dropped to normal, and blood pressure was normalized. For early improvement of hypertension, the patient should enter a low sodium diet. If ACTH is quickly suppressed, DOC secretion is subsequently reduced. The lack of 11-hydroxylase and the inability to synthesize aldosterone can also lead to hyponatremia and hypovolemia, so the treatment should not be too hasty. Glucocorticoid dose adjustment is still based on the intermediate metabolites (more conveniently, whether 17-OHCS returns to normal as the control standard) and the growth curve.
17α-hydroxylase deficient type
[Clinical manifestations]: This type is rare, and most patients are seen at puberty for primary amenorrhea or delayed puberty. In females, there is no breast development until puberty, no axillary or pubic hair, no menstruation, juvenile vulva style, thin and tall body type, and dark complexion. Males (46, XY) tend to be cultured as females due to the absence of testosterone in the embryonic period and female-like or partially masculinized external genitalia. However, there is no uterus or fallopian tubes, and the testes are located in the groin or abdominal cavity. There is often varying degrees of hypertension during adolescence, with some developing hypertension at the age of 7-8 years, and individuals with severe hypertension, for which the usual antihypertensive drugs are difficult to work. Hypokalemia is common, and patients often have weakness, fatigue, nocturia, or even paralysis, with delayed epiphyseal fusion that stays in adolescence. There are no signs of hypoadrenocorticism due to being compensated by very high corticosterone. A few atypical cases may show normotension, and a few show hermaphroditism.
Diagnosis and differential diagnosis]: This type is characterized by hypertension, hypokalemia, hyporenin, and aldosterone can be low, normal, or high, clinically resembling primary aldosteronism. However, this sign has the following features to differentiate: ① hypertension, hypokalemia paralysis seen in prepubertal period. (2) Hypertension, hypokalemia with primary amenorrhea and sexual naïveté found after puberty, in males of genetic sex (46, XY) with a female phenotype. Primary aldosteronism without sexual infantilization, onset mostly between 30 and 50 years of age. Blood progesterone, corticosterone (compound B), and DOC are measured to be elevated. Urinary 17-KS and 17-OHCS excretion is decreased, while TH(tetrahydro)B and TH(tetrahydro)DOC are increased. Compound B and DOC can be suppressed after one week of low dose dexamethasone. It must also be distinguished from other causes of male pseudohermaphroditism or female infantilism: anti-androgen syndrome, 5α-reductase deficiency, cholesterol chain-breaking enzyme defect, 3β-hydroxysteroid dehydrogenase defect, 17-ketosteroid reductase defect, testicular or ovarian hypoplasia, which are usually not associated with hypertension and hypokalemia, and thus are not difficult to distinguish from this syndrome. In the case of testicular hypoplasia, the uterus and fallopian tubes are still present due to the lack of paramedian tubular inhibitory factor and androgens. 1lβ-hydroxylase defect has hypertension and hypokalemia, but the clinical manifestation is female pseudohermaphroditism and male pseudosexual precociousness, which is very different from the sexual infancy of this sign.
【Treatment】: Dexamethasone is preferred. The starting dose, 1, 5mg/24h, is given orally in divided doses. The dose should be adjusted according to the blood B, DOC and ACTH level to make it reach or close to the normal level. The dose should not be too high, when plasma renin activity – angiotensin II (PRA-AT II) is inhibited, such as compound B, DOC suddenly drop, blood aldosterone and not in time to resume secretion, making the salt corticosteroids significantly insufficient and hypotension, hyperkalemia. Therefore, if there is a tendency of hyperkalemia, 9α fludrocortisone 0,1mg/24h should be administered immediately to avoid cardiac rhythm disturbance caused by hyperkalemia. In addition, attention should be paid to Cushing’s syndrome caused by excessive doses due to long-term treatment. In a few patients, the biochemistry is normalized, but the blood pressure is not normalized, so anti-hypertensive drugs can be combined.
If the phenotype and genetic sex are female, estrogen replacement therapy should be added to promote the development of breast and external genitalia, so as to make the female body appear. Testosterone can also be used to stimulate pubic hair growth in appropriate amounts. If the phenotype is female and the genetic sex is male (46, XY), the treatment should be based on the gender of the patient and the inguinal or intra-abdominal testes should be removed, as these testes are more likely to be malignant, followed by estrogen replacement therapy. If there is clitoral hypertrophy, excess portion of the clitoris should be removed and vaginoplasty should be performed if necessary.
3β-hydroxysteroid dehydrogenase defect
Defective 3β-hydroxysteroid dehydrogenase is rare. The enzyme defect involves both the adrenal glands and the gonads (ovaries and testes), and the male embryo cannot produce enough testosterone, resulting in incomplete masculinization at birth, hypospadias, cryptorchidism, and even male pseudohermaphroditism. Females may have mild clitoral hypertrophy and fused labia majora due to high dehydroepiandrosterone (DHA) production and partial conversion to testosterone in the surrounding tissues. Dark skin in infants is associated with primary hypoadrenalism and increased ACTH. Due to severe deficiencies of salt corticosteroids and glucocorticoids, adrenocortical insufficiency is manifested after birth: anorexia, nausea, vomiting, sodium loss, water loss, and finally death due to circulatory collapse.
Mild atypical 3β-hydroxysteroid dehydrogenase deficiency accounts for about 10% to 15% of the disease. It is similar to 21-hydroxylase deficiency in its late form, with no abnormal findings at birth and onset mostly in adolescence, and masculinization in females similar to 21-hydroxylase deficiency, which is one of the causes of pubertal hirsutism in females. Since DHA is converted to testosterone in peripheral tissues, males have sufficient masculinization by puberty, and after ACTH excitation, 17-hydroxyl, Δ5 pregnenolone and DHA increase significantly, and 17-hydroxyl, Δ5 pregnenolone/17 hydroxyprogesterone and 17-hydroxyl, Δ5 pregnenolone/cortisol ratios are higher than normal, according to which the diagnosis can be confirmed. In some cases of 3β-hydroxysteroid dehydrogenase deficiency, blood 17-hydroxyprogesterone is very high, close to the level of 21-hydroxylase deficiency, due to the peripheral transformation of high levels of 17-hydroxyprogesterone. The only differentiation is the increased ratio of 17-hydroxyprogesterone, Δ5 pregnenolone to 17-hydroxyprogesterone.
Treatment is still based on glucose and salt corticosteroid replacement therapy. Even if diagnosed and treated early, most of them inevitably die in early childhood. Patients have hepatic impairment, probably due to severe type 1 enzyme deficiency, which is also responsible for death. A few mild cases survive, with adequate masculinization in males up to puberty, as DHA can be converted to strongly active testosterone in the liver, and hirsutism or mild masculinization in females at puberty. If dexamethasone 0,5 mg, qd is given, hirsutism can improve and regular menstruation can occur. Treatment of mild pediatric patients must be treated with great caution and a thorough endocrine examination must be performed before making a decision, as glucocorticoids have a significant inhibitory effect on growth in children.
P450scc defects (lipoid adrenal hyperplasia)
Due to defective 20:22 charcoal chain enzyme, 20-hydroxylase or 22-hydroxylase, the conversion of cholesterol to pregnenolone is blocked, thus preventing the synthesis of glucose, salt corticosteroids and sex hormones. Regardless of genetic sex, male or female, all external genitalia are female or nearly female at birth. In males, the testes can be found in the groin or abdominal cavity. Immediately after birth, hyperalgesic crisis develops with marked skin pigmentation, anorexia, nausea, vomiting, diarrhea, weight loss, dehydration, and low urinary 17-OHCS and 17-KS. Due to lack of glucocorticoids, immune insufficiency, and frequent infections, many deaths occur in infancy even with immediate administration of cortisol and DOCA. Autopsy showed enlarged adrenal glands with yellow, foamy sections and intracellular lipid-like cells.