In congenital adrenal hyperplasia, the most important and common cause of DSD, the female embryo is virilized by abnormal androgens. Congenital adrenal hyperplasia also occurs in males, but the excess adrenal androgens do not interfere with sexual development. An enzyme block in the conversion of cholesterol to cortisol and aldosterone causes low levels of cortisol in the blood of the fetus. This reduces the normal feedback inhibition of the hypothalamic secretion of corticotrophin-releasing factor. Conseq­uently, the hypothalamus secretes abnormally high amounts of corticotrophin-releasing factor, thus stimulating the pituitary to produce excessive adrenocorticotrophic hormone (ACTH) and melanin-stimulating hormone. The high levels of ACTH stimulate the enzymes in the pathway for cortisol synthesis, leading to hypertrophy of the fetal adrenals. The usual enzyme deficiency which prevents cortisol from being produced (i.e. 21-hydroxylase), diverts precursor molecules into side pathways which lead to androgen synthesis. This abnormal androgen synthesis in the presence of excess adrenal function leads to the virilization of female embryos. Lack of aldosterone, which occurs in some enzyme deficiencies, causes loss of sodium chloride from the kidney and leads to severe dehydration, which usually presents in the second or third week of life with sudden collapse (the so-called salt-wasting crisis). Failure of cortisol secretion produces an infant with low resistance to stress, so that even trivial infections will induce severe vomiting, diarrhoea and dehydration. Occasionally, less common enzyme deficiencies lead to excess production of deoxycorticosterone and induce hypertension (Fig. 22.3).

The other DSD common in females is failure of ovarian development caused by Turner syndrome, but in these children the external genitalia are normal female because external genitalia will develop a female appearance in the absence of any hormone. Babies with Turner syndrome may be identified clinically by growth retardation and a webbed neck. The fetal lymphatics in Turner syndrome are abnormal: lymphangiomatous development, which occurs in the cervical lymphatics, leads to the redundant folds of skin of the neck. Lymphangiomatous maldevelopment elsewhere in the fetus with Turner syndrome may be seen on the dorsum of the hands and feet. Therefore, a baby born with oedematous or puffy feet should be investigated for Turner syndrome if the genitalia are normal female in appearance.

Disorders of sex development may be produced by dysplastic testes. One or both testes may be affected. When both testes are dysplastic, defici­ency of androgen may cause incomplete virilization of the external genitalia, and deficiency of Műllerian inhibiting substance may allow preservation of Műllerian duct structures (i.e. uterus and tubes). Usually, both gonads are undescended because they are unable to secrete the hormone(s) necessary for testicular descent.