Histological changes due to chronic ACTH elevation and systemic changes due to lack of cortisol products. Elevated ACTH is caused by low levels of cortisol, and decreased cortisol is due to a deficiency or lack of one of the five enzymes necessary for the synthesis of cortisol from cholesterol. Blockage of each enzyme causes a characteristic deficiency and accumulation of a certain adrenal hormone precursor. In the common type of congenital adrenal hyperplasia (CAH), the blocked enzyme has a pre-metabolic volume that accumulates in the vicinity and is metabolized to adrenal androgens via a bypass. Congenital adrenal hyperplastic masculinization occurs when an enzyme block (e.g., 21-hydroxylase deficiency) causes androgen accumulation, resulting in varying degrees of masculinization in the affected female fetus. If the blocked enzyme reduces androgen synthesis, it causes hypermasculinity, leading to hypermasculinity in affected male fetuses. Several autosomal recessive disorders can cause CAH. because the external genitalia of affected infants are indistinguishable between the sexes, hypermasculine male infants and hypermasculine female infants are difficult to distinguish by physical examination and only provide some clues to the initial diagnosis. The typical presentation is a penis-like structure, longer and larger than the clitoris but smaller than the penis, with a single urogenital sinus opening at the base of this penis and varying degrees of incomplete fusion of the labial and scrotal folds. A basal 17-hydroxyprogesterone level >8ng/ml confirms the diagnosis of CAH caused by 21-hydroxylase. to differentiate between the different causes of CAH an ACTH stimulation test is required. The levels of adrenal hormone precursors are measured before the intravenous injection of 250 μg of synthetic ACTH, and 30 minutes after the injection. The elevation of the different precursors and the ratio between them help to diagnose each enzyme defect. A few enzyme defects (e.g., late-onset 21- or 11-beta-hydroxylase deficiency) do not show significant masculinization until late childhood, puberty, and adulthood. Symptoms include enlarged clitoris or penis, hirsutism, seborrheic dermatitis, low voice, accelerated height growth but premature epiphyseal closure (growth plates on long bones) eventually leading to short stature, strong muscles, temporary baldness, amenorrhea, and menorrhagia in adults. 21-hydroxylase deficiency 90% of CAH is caused by this enzyme deficiency. The incidence ranges from 1/10,000 to 1/15,000 live births. There is an increase in products such as progesterone; 17-hydroxyprogesterone; dehydroepiandrosterone (DHEA), a weaker androgen that masculinizes affected female infants; and androstenedione, accompanied by low or absent levels of plasma cortisol and aldosterone. The urinary metabolites of these precursors (17-ketosteroids and progesterone triol) were higher than normal. Reduced aldosterone secretion leads to low sodium and high potassium due to salt loss, with a consequent increase in plasma renin activity. In the case of partial deficiency of the enzyme, which does not show aldosterone deficiency, the patient’s sodium and potassium remain normal. There is a greater likelihood that this is related to a single type of HLA. Diagnosis and treatment during pregnancy is not effective. Carriage status (heterozygous) can also be diagnosed in childhood and adulthood. Treatment of 21-hydroxylase deficiency is by glucocorticoid replacement (hydrocortisone, cortisone acetate or prednisone) and, if necessary, by salt corticosteroid replacement to achieve a dynamic balance of sodium and potassium. The oral dose of hydrocortisone (15-25 mg/m2 per day in 3 doses) or prednisone (3-4 mg/m2 per day in 2 doses) is adjusted to maintain adrenal androgen precursors in the appropriate age range. Intravenous cortisone acetate at 18-36 mg/m3 every 3 days may also be used in infants who have failed oral therapy. The aim of treatment is to normalize plasma androstenedione, 17-hydroxyprogesterone and plasma renin activity and to normalize urinary metabolites (17-ketosteroids and progesterone triol) as well. Oral fludrocortisone (0.1 mg/d) may be given if there is salt loss. Infants often require oral salt supplementation. Close monitoring is required during treatment. Overtreatment with glucocorticoids can lead to medically induced Cushing’s syndrome, which is characterized by childhood obesity, abnormal growth, and delayed bone age. Inadequate glucocorticoid therapy leads to failure of ACTH suppression, resulting in hyperandrogenism, which is manifested by androgenesis and hyper-growth in childhood, and eventually cessation of growth due to precocious puberty and eventual short stature. Compliance with treatment must be maintained, growth must be closely monitored and bone age must be read annually. Affected girls require surgical reconstruction to reduce the clitoris and create a vaginal opening. Further surgery is usually performed in adulthood, and with proper care and attention to psychosexual issues, a normal sexual life and fertility can be expected. 11β-hydroxylase deficiency 3% to 5% of CAH is caused by this enzyme deficiency. The characteristic steroidal manifestation is elevated 11-deoxycorticosterone (and 17-hydroxycorticosteroids in the urine). Due to the salt corticosteroid activity of hydroxycorticosteroids, patients exhibit salt retention and hyperkalemic hypertension. Plasma renin activity is low. Masculinization may occur. Treatment is with cortisol replacement and must also have salt corticosteroid replacement. 3β-hydroxysteroid dehydrogenase deficiency This rare abnormality leads to accumulation of DHEA and its peripheral conversion to testicular androgens in the extra-glandular tissues. Treatment is also with glucocorticoids and salt corticosteroids when necessary. Cholesterol-carbon chain enzyme deficiency and 17-alpha hydroxylase deficiency These abnormalities lead to masculinization in affected female infants and hypermasculinization in affected male infants. Corticosteroid 18-methyl oxidase type II deficiency manifests as a typical aldosterone deficiency: chronic hyperkalemia and low plasma aldosterone. No sexual differentiation abnormalities are present.