Introduction
basic introduction
21 hydroxylase deficiency(21-hydroxyulase deficiency) is the first, most studied and most common type of congenital adrenal hyperplasia. This enzyme deficiency leads to a decrease in glucocortico and/or salt corticosteroids, an increase in ACTH and androgen secretion, and masculinization in patients. And salt loss symptoms, life threatening in severe cases. The incidence rate is about 1 in 500 in the Eskimos, and 1/2 to 1 in 50,000 in the Caucasian and Yellow.
21-hydroxylase deficiency isCongenital adrenal hyperplasia syndromeThe most common one, accounting for 90% to 95% of the total number of patients, the incidence rate is very inconsistent. Switzerland is 1/18500, Britain is 1/5000, and Maryland is 1/67,000, with a male to female incidence ratio of 1:4.
Pathogenesis
1. Function of CYP21 enzyme: CYP21, a cytochrome 450C hydroxylase, which obtains electrons from NADPH via flavoprotein-P450 reductase and oxidizes 17-hydroxyprogesterone (17-OHP) to 11-deoxidized cortisol, the latter The cortisol is synthesized by 11-hydroxylation. During mineralocorticoid synthesis, CYP21 catalyzes the conversion of progesterone to 11-deoxycorticosterone.
2. CYP21 gene mutation: The CYP21 gene is located at 6p and is located between the HLA-B and HLA-DR genes. CYP21 and HLA loci have a genetic advantage of linkage. In the affected family, homozygous, heterozygous or non-affected individuals can be identified by analyzing HLA type. Patients with CYP21 deficiency have been found to have various HLA antigens and haplotypes. For example, patients with salt-deficient CYP21 deficiency have a high frequency of HLA-B47, while DR1 and B14 are more common in non-classical patients.
CYP21 has two genes, CYP21B and CYP21A, in each chromosome 6, only CYP21B has biological functions, and CYP21A is a pseudogene. The CYP21B and CYP21A genes are approximately 3.3 kb in length with 10 exons and 98% sequence homology. Their arrangement is from the far centromeric end of the chromosome to the near centromere: C4A-CYP21A-XA-C4B-CYP21B-XB. This tandem arrangement causes unbalanced pairing during meiosis, duplication or Missing error. About 95% of the mutations are recombination errors between CYP21B and CYP21A, about 15% are large deletions of CYP21A exons 3~8 integrated into the same region of CYP21B, and about 80% of patients have gene conversion mutations, usually CYP21A The clip is converted to CYP21B. There are also some patients who have proven to be true point mutations with no gene conversion. These mutations cause a decrease in 21-hydroxylase activity, or no activity at all. For example, the Ilel72Asn mutation has a clinical manifestation of simple masculinization. The enzyme activity test found that only 3% to 7% of normal people, but there is still sufficient aldosterone secretion, so no salt loss symptoms occur. Loss of salt type has a serious loss of enzyme activity, while the activity of non-classical enzymes is more preserved.
Clinical manifestation
Simple masculine
Only the CYP21 involved in the cortisol synthesis pathway is involved, and the aldosterone synthesis pathway is normal.
1 Female patients have different degrees of genital external genitalia (from clitoris hypertrophy to labia majora fusion, forming part of the penis urethra). Severe cases usually have genital sinus retention (there is only one opening in the vagina and urethra). Ovary, uterus and fallopian tubes are present, and the epididymis and vas deferens are absent. Another effect of increased androgen levels is to accelerate the body's linear growth, height is higher than that of children of the same age, and bone age is advanced. Excessive ACTH can cause skin pigmentation.
2 male patients showed non-gonadotropin-releasing hormone (GnRH)-dependent precocious puberty, penis enlargement, pubic hair growth, but testes and gonadotropins remained at prepubertal levels. Skin pigmentation and linear growth of the body are accelerated in the same way as female patients.
Loss of salt
Both CYP21, a synthetic pathway for both cortisol and aldosterone, are involved. In addition to the clinical manifestations of masculine type, neonatal patients also have the performance of water and salt imbalance; such as refusal, vomiting, dehydration, shock. If not treated in time, the mortality rate is very high. Most patients with salt-loss type develop from 1 to 5 weeks after birth, and there are very few cases after 6 weeks.
21 hydroxylase deficiency
Non-classical
1 asymptomatic: also known as recessive CYP21 deficiency. In the classical CYP21 deficiency family, some members showed no masculinity, but the serum CYP21 catalytic reaction step increased the level of precursor steroid 17-OHP.
2 delayed hair: the external genitalia is normal at birth, there is no masculine change. In the prepubertal period, hairy, hemorrhoids, linear growth of the body and bone age are advanced.
Type
Clinically, the 21 hydroxylase deficiency is divided into 4 types according to the severity of the disease and the age of onset:
1) Simple masculine type: Partial deficiency of 21-hydroxylase.
2) Male morphing with salt loss: a complete lack of 21-hydroxylase.
3) Concealed type: no abnormal signs, blood 17-hydroxyprogesterone and androstenedione were normal or slightly higher, both of them increased after ACTH stimulation, but lower than the above two types.
4) Late hair style: normal development before puberty, hairy after puberty, rare menstruation and masculinization.
Auxiliary inspection
1. Simple male type: serum 17-OHP, androstenedione andTestosteroneThe level of urinary 17-ketosteroid (17-KS) and 17-ketogenic steroid (17-KGS) increased, serum electrolytes and aldosterone levels were normal, and PRA was normal or slightly elevated. The karyotype is normal.
2. Loss of salt type: serum and urinary adrenocortical steroid spectrum is the same as masculine type, plasma aldosterone level is decreased, PRA level is significantly increased, hyponatremia, hypoglycemia, hyperkalemia, metabolic acidosis. The karyotype is normal.
3. The basal level of asymptomatic serum 17-OHP, androstenedione and testosterone or the level of ACTH excitatory increased, and the levels of urinary 17-KS and 17-KGS increased.
4. Late onset: similar to asymptomatic.
Female pseudohermaphroditism and male non-GnRH-dependent precocious puberty should be considered for the possibility of CYP21 deficiency. Laboratory tests revealed increased urinary 17-KS and 17-KGS flux and/or serum 17-OHP and androstenedione levels. Increase can confirm the diagnosis.
Treatment
1. Treatment of acute adrenal crisis (loss of salt)
(1) Immediately establish an intravenous channel, instilling isotonic saline, such as low blood pressure, rapid infusion of isotonic saline 20ml per kilogram of body weight.
(2) Hypoglycemia: Immediately intravenous bolus glucose 0.25g/kg.
(3) Hydrocortisone sodium succinate 50mg/m, intravenous bolus, then 50~100mg/m intravenous infusion for 24h.
(4) hyponatremia and hyperkalemia: 9α-fludrocortisone 0.1 mg, nasal feeding. The dose and number of hydrocortisone doses were determined based on serum electrolyte levels, degree of dehydration, and blood pressure status.
2. Maintenance treatment
(1) Glucocorticoid: 20 to 25 mg/kg of cortisone acetate in patients under 2 years old, intramuscular injection, continuous 5 days, 1.5 to 20 mg later, intramuscular injection once every 3 days. In case of stress, change to daily injection. The dose of cortisone varies from person to person. During the treatment, the dose should be adjusted at any time according to the patient's clinical manifestations, 24h urine 17-KS displacement, bone age and body straight growth rate.
Replacement therapy from 2 years old to prepubertal patients to oral preparations.HydrocortisoneTake 18mg/m daily, or cortisone acetate 22mg/m daily, in 3 divided doses.
After puberty: Long-acting glucocorticoid preparations can be used instead. Daily dose:Prednisone3.7mg/m, methylprednisolone 2.4mg/m orDexamethasone0.23 mg/m. Take it in divided doses. Alternative treatments for glucocorticoids are needed for life.
(2) Mineralocorticoid: In addition to glucocorticoids, patients with salt-loss need to supplement mineralocorticoids. Fluorocortisone 0.05~0.3mg/d, orally. At the same time, the intake of salt 1 ~ 3g / d, in order to maintain serum electrolytes, PRA and blood pressure in the normal range of principles.
(3) External genital plastic surgery: Female patients with clitorisplasty should be performed after the treatment is stable and before the age of one. Vaginal angioplasty can be done in adulthood.
Disease prognosis
1. Correct replacement therapy can result in normal menstruation and fertility in simple masculine women.
2. The adult height of male and female patients after replacement therapy still does not reach the normal level.
3. Female patients have a small vaginal opening, reduced interest in the opposite sex and decreased libido. Married people have low fertility, especially those who lose salt.
4. Interruption of treatment in female patients is prone to polycystic ovary, progressive masculinization, and premature closure of the epiphysis.
5. Disruption of treatment in male patients is prone to residual adrenal cell proliferation, pituitary hyperplasia, adrenal tumors, and adrenal cortical crisis.
6. Excessive treatment of male and female patients can cause kushen syndrome, growth arrest, obesity and osteoporosis.
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