Congenital adrenocortical hyperplasia is a group of diseases caused by enzyme defects in the adrenocortical hormone synthesis pathway, which is an autosomal recessive disorder with an incidence of 1/16,000 – 1/20,000 in newborns.
I. Clinical manifestations
The clinical manifestations depend on the site of the enzyme defect and the severity of the defect. There are several common types as follows.
1. 21-hydroxylase deficiency is a common type of congenital adrenocortical hyperplasia, accounting for 90%-95% of the disease. 21-hydroxylase gene is located on the short arm of chromosome 6, closely linked to the HLA gene family, and consists of two motifs, the A gene and the B gene. CYP21B, also known as CYP21, is the gene encoding 21-hydroxylase; CYP21A, also known as CYP21 mutations, including point mutations, deletions and gene conversions, result in partial or complete deficiency of 21-hydroxylase.
Due to insufficient cortisol synthesis and secretion, the pituitary gland secretes large amounts of ACTH to stimulate adrenal cortex hyperplasia, and at the same time, androgen synthesis is excessive, resulting in clinical symptoms of varying severity, which can be manifested in three types: simple masculinization type, salt loss type, and atypical.
(1) Simple masculinization type: 21-hydroxylase is incompletely deficient, the enzyme deficiency is moderate, 11-deoxycortisol and 11-deoxycorticosterone cannot be synthesized normally, and its precursors 17-hydroxyprogesterone, progesterone and dehydroisoprogesterone are increased, but because the affected children still have residual 21-hydroxylase activity, a small amount of cortisol and aldosterone can be synthesized, so there are no clinical symptoms of salt loss, and the main manifestation is androgen The main symptoms and signs of androgen increase.
Girls show pseudohermaphroditism. Because steroid hormone synthesis defects exist in the fetus, girls show varying degrees of masculine signs at birth, such as an enlarged clitoris that resembles the following urethra in males; labia majora that resemble a boy’s scrotum, but without testicles; or labial fusion of varying degrees. Although the external genitalia are hermaphroditic, the internal genitalia are still female, with ovaries, fallopian tubes, and uterus. Pubic hair and axillary hair may appear at the age of 2-3 years. At puberty, there is a lack of female sexual characteristics, breast development and menstruation.
Boys show pseudo-precocious puberty. They may be asymptomatic at birth and show signs of precocious puberty after 6 months of life, with general hair, whiskers, seat sore throat nodes, low voice and muscular development. Both boys and girls show excessive physical growth, bone age beyond age, and their most K short stature due to premature epiphyseal fusion. Due to increased ACTH, there may be skin and mucous membrane pigmentation. Generally, the more severe the defect, the more obvious the increase in pigmentation, with skin folds as obvious, such as the groin, around the areola, axillae, finger joints stretching surface even, etc. Newborns mostly show in the areola and external genitalia.
(2) Loss of salt type: It is caused by complete lack of 21-hydroxylase. The secretion of precursor substances of cortisol such as progesterone and 17-hydroxyprogesterone increases, while the synthesis of cortisol and aldosterone decreases, causing the distal renal tubules to shoot too much sodium and excrete too little potassium. In addition to the above-mentioned masculine manifestations, children may have food refusal, vomiting, diarrhea, weight gain or loss, dehydration, hyponatremia, hyperkalemia, and metabolic acidosis soon after birth. If treatment is not timely, death can occur due to circulatory collapse. Female children are born with hermaphroditism, which is easy to diagnose. Male children are more difficult to diagnose, often misdiagnosed as pyloric stenosis and operated on, or misdiagnosed as infantile diarrhea and delayed treatment.
(3) Atypical type: also known as late-onset, insidious or mild form, is due to a mild deficiency of 21-hydroxylase. The clinical manifestations of this disorder vary, and the age of onset varies.
2.11β-hydroxylase deficiency accounts for about 5-8% of the disease. In this enzyme deficiency, androgens and 11-deoxycortisol are increased. Clinical manifestations are similar to masculinization symptoms out of 21-hydroxylase deficiency, but to a lesser extent; hypertension and sodium retention may be present.
3.3β-hydroxysteroid dehydrogenase deficiency This type is rare and is due to mutations in the 3β-HSDII gene.
4.17α-hydroxylase deficiency This type is also rare
Laboratory tests
1.Biochemical tests
(1)Urine 17-hydroxysteroids, 17-ketosteroids and progesterone triol measurement
(2) Measurement of blood 17-hydroxyprogesterone, renin angiotensinogen, aldosterone, dehydroisosterone, deoxycorticosterone and testosterone, etc.
(3) Blood electrolyte measurement: hyponatremia and hyperkalemia may be present in the salt loss type.
(4) Measurement of blood cortisol and ACTH
(5)Sex hormone measurement
2.Other tests
(1)Chromosome examination
(2)X-ray examination
(3)CT or MRI examination
(4)Genetic diagnosis
III. Treatment
The objectives of treatment of this disease are.
1.Replace the deficiency of adrenal secretion of steroids, replenish the physiological needs of glucose and salt corticosteroids, and maintain the normal physiological metabolism of the body;
2. Inhibit the secretion of ACTH, thus reducing the excessive secretion of adrenal androgens, inhibiting masculinization, preventing accelerated epiphyseal maturation, and promoting normal growth and development.
1. For children with salt loss, water and electrolyte disorders should be corrected in time. Intravenous rehydration can be done with saline, or with 0.45% sodium chloride and sodium bicarbonate solution in case of metabolic acidosis. For severe salt loss, 25-100mg of hydrocortisone should be injected intravenously.
2.Long-term treatment
(1)Glucocorticoid
(2)Salt corticosteroid
In the process of corticosteroid treatment, children with salt loss should also be tested for potassium, sodium and chloride to adjust the dosage of hormone. The dose of glucocorticoids should be increased 1.5-2 times than usual when the child is under stress (such as infection, excessive fatigue, surgery, etc.) or during puberty.
3.Surgical treatment Male children do not need surgical treatment. In female children with pseudohermaphroditism, partial clitoridectomy or orthopedic surgery is recommended at the age of 6 months to 1 year.
Prevention
1.Newborn screening Early diagnosis can be made by using the dried blood drop paper method and collecting heel blood samples from infants 2-5 days after birth to test the concentration of 17-OHP.
2.Prenatal diagnosis
(1) 21-OHD: take chorionic villus biopsy for fetal cell DNA analysis at 9-11 weeks of gestation; take amniotic fluid at 16-20 weeks of gestation to detect pregnancy triol, 17-OHP, etc. Since most children with atypical 21-OHD do not have significantly elevated levels of 17-OHP after birth, genetic testing is the only means of early diagnosis for this type of child.
(2) 11β-OHD: amniotic fluid DOC or chorionic villus can be taken for related genetic analysis for diagnosis.