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Gonadal Dysgenesis

Incomplete differentiation of the bipotential gonad into either an ovary or a testis (partial gonadal dysgenesis) is one of the most frequently encountered causes of genital ambiguity. Dysgenic testes may secrete insufficient amounts of both testosterone and MIS (resulting in incomplete masculinization of the genital tubercle and persistence of mullerian structures) gonadal dysgenesis.

Internally, 75% of patients with partial XY gonadal dysgenesis have a uterus because neither gonad produces enough MIS. In most cases of partial gonadal dysgenesis, the karyotype is mosaic 45,X/46,XY, but a range of karyotypes is seen. One gonad is usually a streak (a tiny gonad with ovarian stroma and no ova), and the other is likely to be a fairly well-developed testis in which Leydig cells can usually be identified. In the complete form of XY gonadal dysgenesis, both gonads are streaks.

True Hermaphroditism.

When the gonads in one individual are comprised of both ovarian and testicular elements, the condition is called true hermaphroditism. The most common gonad found is an ovotestis, and gonads with purely ovarian tissue are more likely to be found on the left side. In most cases, any testicular tissue found is dysgenetic, and the ovarian tissue is normal. Most patients with true hermaphroditism have ambiguous genitalia. Between 50% and 97% of patients with true hermaphroditism are 46,XX or mosaic. In addition, true hermaphroditism may be familial. On the basis of extensive studies carried out.

The exact nature of true hermaphroditism is puzzling. In general, germline SRY mutations have not been found in 46,XX subjects, but there are exceptions. In SRY mutation-negative cases, the most likely explanation for true hermaphroditism is inappropriate activation of testicular differentiation at a post SRY stage in some parts of the gonad. One group has reported finding a postzygotic somatic mutation in the SRY gene in the gonad but not the blood. Studies of XY gonadal hermaphroditism in an experimental animal model show that both true hermaphroditism and partial gonadal dysgenesis can stem from a common etiology and seem more like different parts of the same spectrum than distinct and separate disorders.

21-Hydroxylase Deficiency.

If the patient has an XX karyotype and ambiguous genitalia, the most likely diagnosis is congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. This condition results in increased ACTH secretion, which, in turn, results in hyperpigmentation of the genital skin. An infant with both ambiguous genitalia and hyperpigmented genital skin has impaired adrenocortical function until proven otherwise. The milder forms are more common.

On the basis of data collected during neonatal screening, the incidence of 21-hydroxylase deficiency is 1 in 14,500. Only affected females have ambiguous genitalia, which is caused by the ACTH-stimulated hypersecretion of adrenal androgens. Development of the ovaries and internal female reproductive organs is unaffected. Because enzyme activity is reduced to practically zero in the salt-wasting form and to approximately 1% in the simple virilizing form, the conversion of 17alpha-hydroxyprogesterone to 11-deoxycortisol and of corticosterone to desoxycorticosterone is impaired. Three quarters of affected infants have the severe salt-losing form, which is associated with vomiting and, from about 7 days after birth, signs of hyponatremic dehydration and hyperkalemia. Without prompt and appropriate treatment (intravenous rehydration and replacement of electrolytes, hydrocortisone, and mineralocorticoid), the condition is fatal. The gene for 21 hydroylase is termed CYP 21.

17beta-Hydroxysteroid Dehydrogenase Deficiency.

This defect impairs the conversion of androstenedione to testosterone in the testis. Sixty cases have been reported from one inbred community in the Gaza Strip. Inheritance is autosomal recessive. Most XY cases have either ambiguous or female genitalia. In that group, at least 14 mutations in the 17beta-hydroxysteroid reductase 3 gene have been detected. In infancy and childhood, the diagnosis of partial androgen insensitivity may be incorrectly made unless a human chorionic gonadotropin (hCG).

5alpha-Reductase Deficiency.

In androgen target tissues, particularly those of the external genitalia and male beard area, testosterone undergoes intracellular conversion to the more potent androgen, 5alpha-dihydrotestosterone (DHT) before binding to the AR.