Disorders of hormone production in 21-hydroxylase deficiency.
Due to the increase in androgens, classical CAH leads to virilization of the female genitalia even before birth. Depending on the severity of the 21-hydroxylase deficiency, it can occur with or without a salt-wasting syndrome. Salt wasting leads to developmental disturbances and can result in shock or coma in infancy. In boys, classical CAH manifests only as a salt-wasting syndrome.
Renin is produced and released in the kidneys when blood pressure drops. Renin itself is an enzyme (protease) that cleaves angiotensinogen in the blood. The cleavage product, angiotensin I, is converted into angiotensin II by angiotensin-converting enzyme. In the adrenal glands angiotensin II receptors initiate the cascade leading to aldosterone production. Aldosterone inhibits the excretion of sodium in the kidneys and increases the excretion of potassium. A deficiency of aldosterone results in sodium loss. Depending on the severity of the 21-hydroxylase deficiency, this leads to reduced aldosterone production with salt wasting.
ACTH also stimulates the production of aldosterone in the adrenal glands. However, its primary effect in the adrenal gland is the production of cortisol.
Clinical Symptoms:
In girls, masculinization (virilization) occurs in the uterus due to androgens. Classification is based on the Prader scale (0-5). The labia enlarge and fuse with increasing virilization. The clitoris becomes larger, and a urogenital sinus forms, which means a common duct for the urethra and vagina passes through the clitoris (Prader 5).
In untreated or poorly controlled cases, androgens lead to the development of acne, premature pubic hair growth, early voice deepening, absence of menstruation, and other signs of masculinization in girls. Androgens cause premature closure of the bone epiphyseal growth plates, resulting in short stature.
A deficiency of cortisol can lead to hypoglycemia in the first days of life. A deficiency of aldosterone can cause a salt-wasting crisis in the second week of life, characterized by dehydration, low sodium, high potassium levels, and metabolic acidosis.
In some countries, such as Germany, the determination of 17-OH progesterone is included in the legal newborn screening using an immunoassay. However, this method can only detect classical 21-hydroxylase deficiencies. The immunoassay is not always reliable. Therefore, if the screening results are suspicious, it is advisable to determine electrolyte levels (Na, K) on the same day. To confirm the suspicion, if possible, renin concentration, cortisol, 21-deoxycortisol, androstenedione, testosterone, and aldosterone should be measured. 21-deoxycortisol is a metabolite of 17 alpha OH-progesterone and is elevated in patients with CAH (Congenital Adrenal Hyperplasia).
In CAH, potassium, renin, 21-deoxycortisol, androstenedione, and testosterone are elevated, while sodium, cortisol, and aldosterone are decreased. The urinary metabolites of androgens, pregnantriol and pregnantriolone, are elevated.
With these laboratory parameters, the diagnosis of classical CAH can be made through laboratory testing, and treatment can be initiated. Subsequently, a genetic mutation analysis of the CYP21A2 gene can confirm the diagnosis.
Hydrocortisone
In the first few months of life, therapy with 1 mg of hydrocortisone three times daily is usually sufficient in most cases. Hydrocortisone has the least inhibitory effect on growth among all corticosteroids. Therefore, therapy should always be carried out using hydrocortisone during the growth phase. Granulated hydrocortisone is available for infants. Hydrocortisone tablets are typically available in a dosage of 10 mg and can be divided if needed. As the child grows older, the dosage should be adjusted individually based on clinical and laboratory parameters. Hydrocortisone should be divided into three daily doses, with the highest daily dose needed in the morning. The evening dose should not be skipped to avoid unnoticed cortisol deficiency during the night. The substitution dose is approximately 10-15 mg/m2/day. This dosage exceeds the normal daily requirement. This higher dosage is necessary to adequately suppress androgens and to prevent the risk of an Adrenal crisis. During periods of stress or illness, such as fever, the hydrocortisone dose should be increased. For mild illnesses, a double dose is usually sufficient, while severe illnesses often require a fivefold dose. It is better to increase the dose too early and too strongly to prevent an Adrenal crisis. An elevated hydrocortisone dose over a short period has no long-term negative effects.
The treatment of an Adrenal crisis is described in the chapter on adrenal insufficiency.
Every patient with classical CAH should carry an emergency card. The emergency card should contain information on the treatment of an Adrenal crisis and the management during surgeries.
Fludrocortisone
In addition to hydrocortisone therapy, all newborns with CAH should also be treated with a mineralocorticoid (fludrocortisone) since salt-wasting syndrome is very common.
If there is no laboratory or clinical evidence of salt-wasting syndrome, an attempt can be made to discontinue fludrocortisone.
In non-classical CAH, there is residual activity of 21-hydroxylase. Aldosterone production is normal, and cortisol is only slightly impaired. The condition is often noticed in young adulthood, especially in women, during the investigation of increased body hair (hirsutism) due to elevated androgens. Depending on the severity of the enzyme defect, both sexes may experience early puberty (premature pubarche). Elevated androgens can lead to premature closure of epiphyseal growth plates and stunted growth. In girls, menstrual irregularities may occur, and fertility may be limited.
ACTH Test to rule out CAH
The test should be performed in the morning, on an empty stomach, and in the follicular phase of the menstrual cycle for women. A bolus of 25 IU of ACTH (Synacthen 0.25) is administered intravenously. Cortisol and 17 alpha OH-progesterone levels are measured at 0 and 60 minutes. Additionally, DHEA may be determined to rule out a 3-beta HSD defect.
If, after ACTH stimulation, 17 alpha OH-progesterone increases by less than 2.5 µg/l and cortisol increases by more than 150 µg/l, a 21-hydroxylase deficiency is largely excluded.
If the baseline 17-OH-progesterone level is slightly to significantly elevated and increases by more than 2.5 µg/l after ACTH administration and the increase in cortisol is reduced raises suspicion of a heterozygous 21-hydroxylase deficiency (non-classical CAH syndrome). Diagnosis confirmation can be achieved through molecular genetic testing.
If the baseline 17-OH-progesterone level is significantly elevated and increases to > 10 µg/l after ACTH administration, then this raises suspicion of a homozygous 21-hydroxylase deficiency (classical CAH syndrome). Diagnosis confirmation can be achieved through molecular genetic testing.
If DHEA-S is elevated at baseline and increases significantly after ACTH administration, there is suspicion of a 3-beta HSD defect. Diagnosis confirmation can be achieved through molecular genetic testing.
Treatment for non-classical CAH is based on clinical symptoms.
In children with premature puberty, accelerated bone age, and early development, treatment with hydrocortisone is recommended. The dosage must be individually adjusted based on clinical symptoms.
In young women with hirsutism, corticosteroid treatment may not always be necessary. Often, other measures such as anti-androgen oral contraceptives or purely cosmetic measures are sufficient.
In cases of more pronounced symptoms, a low-dose dexamethasone therapy with 0.25 mg at night can be administered.