Screening of 58 neonatal metabolic disorders in Iran (Part 8 - Congenital adrenal insufficiency)

Screening of 58 neonatal metabolic disorders in Iran (Part 8 - Congenital adrenal insufficiency)

Congenital adrenal hyperplasia

The adrenal glands in humans weigh 5 to 7 grams, are conical in shape, and are located in the upper part of the kidneys. These glands are made up of two layers, the cortex and the brain, each of which has a completely different source of embryology.

The cortical part of the adrenal gland is also made up of three layers, which use cholesterol to make three series of hormones called:

 It produces mineralocorticoids, glucocorticoids, and androgens (cholesterol-producing hormones (cholesterol is mostly made available through the blood to the adrenal glands, but small amounts of cholesterol are also synthesized in the adrenal glands themselves).

Glucocorticoids are primarily responsible for activating glucose regeneration reactions. Cortisol is the main glucocorticoid in humans and is responsible for maintaining the body's energy reserves, blood sugar and controlling the body's response to stress.

Mineralocorticoids are responsible for increasing sodium reabsorption, potassium excretion, and H + in the kidneys, and aldosterone is the most important hormone in this group.

Dihydroepiandrosterone (DHEA) is secreted as a precursor to androgens and androstenedone, an androgen hormone, is highly secreted in the cortical part of the adrenal gland (DHEA is converted to the main androgenic hormones in adrenal tissues).

Congenital adrenal hyperplasia, abbreviated CAH, refers to a group of inherited diseases caused by mutations in genes that mediate the production of cortisol-producing enzymes from cholesterol in the adrenal glands.

Congenital conception in this disease also means that this disorder exists from birth.

- This disorder is inherited by the autosomal recessive pattern of heredity and is observed in girls and boys equally. For this reason, it is more common in consanguineous marriages. Carriers of this disease have no symptoms.

More than 95% of CAH cases are caused by a deficiency of the enzyme 21-hydroxylase, which converts progesterone to 11-doxycorticosterone (which has relatively high mineralocorticoid properties) during the production of mineralocorticoids. This enzyme hydrolyzes 17-alpha hydroxyprogesterone and produces 11-doxy cortisol (which is eventually converted to cortisol by the enzyme 11-beta hydroxylase) to produce glucocorticoids.

Cortisol plays a key role in the negative regulation of ACTH secretion, so that a decrease in plasma free cortisol concentration stimulates ACTH secretion from adenohypophysis, which in turn causes hyperplasia (increased number of cells) in the adrenal cortex.

This enzyme is not in the path of androgen synthesis, so if this enzyme has a problem, the synthesis of androgenic precursor steroids will increase significantly and in girls it can cause adrenogenital syndrome.

- Because cortisol is not made in these patients, the amount of ACTH increases and causes hyperplasia of the adrenal cortex and the level of steroid precursors increases hundreds of times normal (in the deficiency of 21-hydroxylase, these precursors are: 17-hydroxyprogesterone and progesterone). .

 With the accumulation of these 17-hydroxyprogesterone deviates towards the androgen biosynthesis pathway, which causes high levels of androstenedione, which is converted to testosterone outside the adrenal gland. This process begins in the fetus at about 8-10 weeks of age and causes the female genitalia to form abnormally.

The gene that produces the enzyme 21-hydroxylase is called CYP21A, and together with the pseudo-gene (false gene) CPY21P, they are located in the short arm of chromosome 6. Both CYP21A and CYP21P have ten exons and are 98% similar.

 The proximity of the site and the structural similarity of the two genes increase the likelihood of mutations due to uneven crossover, and on the other hand, genetic testing makes it difficult to detect enzyme 21-hydroxylase defects. The majority of mutations in this gene are of the conversion type.

- This disease is divided into two types (normal) and unusual (non-classical). In the normal type, the enzymatic defect is more severe and causes symptoms such as masculinization of the external genitalia in girls at birth.

The common type of disease is divided into two types: Salt Wasting (SW) and Simple Virilizing (SV).

- Congenital adrenal hyperplasia due to deficiency of the enzyme 11- Betahydroxylase: The gene for this enzyme is on the long arm of chromosome 8 and is called CYP11B1.

This enzyme normally hydrates 11-doxycycortisol and converts it to cortisol.

In this disease, the amount of corticotropin (11-doxycortisol and doxycorticosterone) is increased and, as in the case of 21-hydroxylase deficiency, increases the production of androgens.

But here the synthesis of aldosterone remains intact and these patients can make aldosterone. These patients have symptoms of adrenal insufficiency such as hypotension, hypoglycemia, hyponatremia, hyperkalemia.

 Two-thirds of them have hypertension, which is a later manifestation. Hypertension is probably caused by an increase in blood levels of doxycorticosterone (DOC).

All of the signs and symptoms of androgen proliferation, which have been reported in 21-hydroxylase deficiency, are also present in these patients. In the blood test of these patients, 11-doxycycline and doxycorticosterone are high.

 Because doxycorticosterone and its metabolites have mineralocorticoid activity, renin-plasma activity is suppressed, so in these patients, although aldosterone production is not significantly altered, aldosterone levels are reduced.

The prevalence of congenital adrenal hyperplasia

The prevalence of classical deficiency is 21- Hydroxylase is about 1 in every 16,000 infants, of which 75% have a salt-loosing form and 25% have a virilizing or maleopausal form.

 The prevalence of this disorder in the United States is 1 in 15,000. Its prevalence is higher in Yupik's Eskimos, from 1 to 300. But it is less common in African-Americans and Asians.


Clinical signs:

The symptoms of clinical phenotype (CAH) depend on the nature and severity of the enzyme deficiency and vary depending on the patient's gender.

Because both aldosterone and cortisol production require a 21-hydroxylation process, in both cases the "salt loss form" of both hormones is deficient.

Symptoms of aldosterone and cortisol deficiency include progressive weight loss, anorexia, vomiting, dehydration, weakness, hypotension, hypoglycemia, hyponatremia, hypercalcaemia, which occurs at about 2 weeks of age, and if If left untreated, the patient will develop cardiac arrhythmias, shock, and death within a few days to a few weeks.

 The main cause of all these symptoms is dehydration.

In males, the formation of the external and internal genitalia is naturally done by testosterone, which is secreted in the fetal testicles.

 Testosterone has no effect on the internal reproductive system of the female fetus, which is made up of mulerin ducts.

 Therefore, female embryos that have been affected by high levels of androgens in the uterus of adrenal origin have a male external genitalia and a female internal genitalia.

 Because testosterone enlarges the clitoris and causes the lips to stick together. The vagina has a joint outlet with the urethra.

The urethra usually opens outwards under the clitoris, and we mistakenly think that the child has hypospadias with cryptorchidism.

In males, mulerin organisms are degraded and do not grow under the influence of the mulerin inhibitor, which is secreted from the testicles.

The severity of virilization is higher in infants of girls with Salt-loosing form deficiency of the enzyme 21-hydroxylase.

The inner part of the genitals of these girls is normal, because they have normal ovaries and because they do not have testicles, they do not secrete the hormone antimullerin.

Boys appear healthy at birth and do not notice the presence of disease until they show clinical signs of adrenal dysfunction, and boys are more likely to die from the disease than girls (the importance of screening at birth).

 Boys who have a simple varicella form are still diagnosed later because they are naturally normal and rarely have adrenal insufficiency.

These people have advanced bone age and are taller than their peers, but premature closure of the epiphyses causes them to stop growing earlier and are shorter in adulthood.

Muscle growth is high, sometimes pubic and axillary hairs, acne and thick voice, penis enlargement, prostate and scrotum are seen, but the testicles are the same size as before puberty and are therefore smaller than other components of the external genitalia.

In girls, although the internal reproductive system is female, the breasts do not grow and do not menstruate unless the production of excess androgen in their body is stopped with the help of treatment.

Children with simple disease varilizans (especially boys) are often undiagnosed until the age of 7-7, when their bone age is 5 years or older and they are generally older than their calendar age.

Boys 21 who are deficient in hydroxylase and have not had enough corticosteroids may develop adrenal rest testicular tumor, which usually regresses with increasing steroid dose and is operated on in resistant cases.

Deficiency of the enzyme 21 hydroxylase is milder in people with the abnormal type, and these people experience symptoms after birth, such as increased androgen activity. Girls with this type of disease do not show masculine traits at birth.

Excessive production of androgens in patients with this disease causes virilization and in some cases loss of salt.

The genital tract of boys with the disease is normal at birth and only increases in pigmentation. But infected girls have ambiguous genitalia, and in most cases their genitals are similar to those of men.

In the other type of disease, there is no loss of salt and only genital ambiguity is observed in female infants, although the severity varies from person to person.

These people do not have problems with the type of salt loss in infancy.

 But in these people, there is an increase in androgen activity and rapid growth in childhood in girls and boys, as well as premature completion of sexual organs with early hair growth in the genital area.

 In the mild and non-classical form of the disease, there are signs of rapid growth as well as early hair growth in the genital area during the period from early childhood to adulthood.

Girls with this type of CAH do not show masculine traits at birth. Some girls will be infertile. Infertility is less common in men.

In the non-classical form, the most important symptom in both sexes is premature puberty.

 
Neonatal screening:

During the screening of metabolic diseases, the level of the hormone 17-hydroxyprogesterone is measured using a calorimetric method. Most screening methods have a low positive predictive value (about 1%), so diagnostic tests are very important in diagnosing false positives.


Method of diagnosis:

Measurement of 17- Hydroxyprogesterone in the neonatal serum sample: This hormone usually increases significantly (the level of this hormone may be high in the first 2-3 days of life and premature infants). Like cortisol, 17-hydroxyprogesterone has a circadian rhythm and is highest in the morning and lowest in the blood at night.

- Stimulation tests: The best way to diagnose the measurement of steroid precursors after stimulation with cosyntropin (synthetic corticotropin).

- Observe an increase in the ratio of androstenedione to cortisol (normally less than 2.5) (

- Observe an increase in the amount of 11-deoxy-cortisol and 21-deoxy-cortisol

- Observe an increase in the ratio of 11-deoxy-cortisol to cortisol (normally less than 1/1)

Clinical symptoms: Patients with Salt-loosing form have symptoms of cortisol and aldosterone deficiency, such as hyponatremia and hyperkalemia, acidosis, and often hypoglycemia, but these symptoms usually last about 1-2 weeks and sometimes longer to show after birth.

Measurement of blood cortisol: In the form of low salt loss, but in the simple virilizane type, it is often normal.

- Other hormonal tests: Androstenedione and testosterone are high in infected girls. Blood testosterone levels are not high in infected boys, as infants normally have higher testosterone than in their later years.

- Renin plasma is high and serum aldosterone is inappropriately low compared to renin plasma levels.

17 Ultraviolet catechosteroids and steroids (17-hydroxyprogesterone metabolite) are high 24-hour urination, but do not require long-term urine testing due to blood tests.

- Sex determination: If there is ambiguity in the genitals to determine the sex of the child, a karyotype test is requested. However, in the case of girls, the injection of contrast agent into the urogenital sinus shows the vagina and uterus and determines the appearance of the girl's internal genitalia.

 

Diagnosis before pregnancy

By examining the enzyme in amniocentesis or umbilical cord blood.

 
treatment:

We treat glucocorticosteroid deficiency with cortisol. This treatment also suppresses the production of androgens by the adrenal cortex and reduces rapid bone growth and virilization.

Treatment is given at a dose of 10-20 mg per square meter of body surface area (oral hydrocortisone is given to the patient three times every 24 hours.

Glucocorticoids should be continued indefinitely in those with a classic deficiency of the enzyme 21-hydroxylase, but this may not be the case in the non-classical type unless there are signs of increased androgen.

 The height of these patients should also be monitored. If the height is higher than the percentage of the curve recorded at the beginning of the treatment, it indicates a lack of treatment, and conversely, a decrease in the height curve is a sign of overdose of glucocorticoids.

Skeletally, the patient's bone age should be monitored. In general, blood levels of 17-hydroxyprogesterone should be maintained above normal, as the patient should receive more corticosteroids to lower it to a normal level.

Children with salt loss (aldosterone deficiency) need to be treated with mineralocorticoids such as fludrocortisone. Its dose in infants is 0.1-3.0 mg twice daily and they also need to receive sodium (1-3 g of chlorhexidine).

 Older children respond to a daily intake of 0.05-1 mg of fludrocortisone.

Hydrocortisone treatment is done with an injection used for 21-hydroxylase deficiency. Temporary mineralocorticoid administration may be necessary during infancy, but is rarely required afterwards.

Hypertension is often relieved by glucocorticoid administration, but if continued, other medications may be needed, in which case antihypertensive drugs from the CCB (calcium channel blocker) group may be helpful.
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Prognosis:

If diagnosed early and treatment is started, the prognosis is good and patients will have a normal lifestyle, so that puberty occurs on time and girls can have a normal menstrual cycle and experience pregnancy.

How to track patients after diagnosis:

Parents of such patients should be taught that they need lifelong treatment and that it is mandatory to follow the nutrition and medication tips of these patients in order to have a normal growth, health and developmental process.

The older siblings of an infected person should be screened for undiagnosed cases.

These patients should be monitored regularly by a metabolic specialist.
Long-term follow-up of the disease should be recommended to parents so that the baby's condition is always healthy. Consultations with a group of counselors, including pediatricians, geneticists, and nutritionists, should also be consulted, and parents should be aware that the slightest violation of the diet can lead to the death of their child.

Genetic counseling is recommended for the molecular diagnosis of the disease and the diagnosis of the type of mutation in subsequent pregnancies (using cells obtained by CVS or amniocentesis).