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Phenotype 1: The XY Female

Complete 46,XY Gonadal Dysgenesis (Swyer's Syndrome)

If the gonad fails to progress beyond the indifferent stage, it may produce no testosterone. Complete XY gonadal dysgenesis usually is diagnosed when a healthy girl of normal stature becomes concerned in her midteens about lack of pubertal development. Eunuchoid skeletal proportions may be found, and the bone age will be delayed. Primary gonadal failure is typical.

Genes Causing Gonadal Dysgenesis.

Chromosomal mosaicism is the cause in most cases; however, in the last 8 years, several genes that regulate gonadal differentiation and testis determination have been discovered, and mutations in several of them have been found in association with gonadal dysgenesis. In 10% to 15% of cases, complete 46,XY gonadal dysgenesis is caused either by a mutation.

Defects in Steroid Hormone Biosynthesis
Deficiency in CYP17 (17alpha-Hydroxylase).

All patients with CYP17 (also called P450 c17 or 17alpha-hydroxylase) deficiency are female regardless of whether they are XX or XY, because there is a complete block in the biosynthesis of androgens and estrogens both prenatally and postnatally. Adrenal hyperplasia results from impairment of cortisol biosynthesis and a secondary elevation in ACTH secretion. Consequently, the secretion of both desoxycorticosterone and corticosterone is greatly elevated, causing hypertension and hypokalemia. Renin activity and circulating aldosterone are both suppressed (except in a Japanese variant).

Lipoid Adrenal Hyperplasia.

In this rare disorder, affected XX and XY infants are phenotypic females who lack the ability to secrete any adrenal or gonadal steroids owing to a complete block.

Because of the apparent absence of cholesterol side-chain cleavage enzyme activity, it was assumed that the defect would reside in the gene encoding P450 scc (CYP11A); however, when this gene was cloned, it was found to be structurally normal.

Complete Androgen Insensitivity Syndrome

Androgen insensitivity syndrome is the most studied of the disorders of sexual differentiation. Women with complete androgen insensitivity syndrome (CAIS) have a normal Y chromosome and fully functioning testes. The androgen receptor in this condition is either absent or unable to bind androgen or transduce the androgenic signal to target genes. XY women with androgen insensitivity syndrome are phenotypically female, with female external genitalia, a short blind-ending vagina.

The diagnosis frequently is made in infancy or childhood because most girls with CAIS have bilateral inguinal hernias containing testes. Alternatively, the girl may seek help in adolescence when menstruation does not occur despite normal breast development. Pubic hair is either completely absent or very sparse. The vagina is usually about 6 cm in length.

Because of the fact that the androgen receptor is on the X chromosome, CAIS is an X-linked disorder. In most cases, a mutation in the coding region of the gene for the AR can be demonstrated, and extensive structure-function studies have been carried out. Similar to all steroid receptors, the AR is a ligand-dependent transcription factor. Mutations in the gene encoding AR may consist of complete absence, large deletions.

Phenotype 2: The XX Male

In this rare condition, the phenotype resembles Klinefelter's syndrome (XXY) in that the testes are small (pealike) and dysgenetic, such that infertility is inevitable. Patients can be normal males or somewhat eunuchoid with gynecomastia. Mullerian structures are absent. The hypothesis that testes develop because of a small Y-to-X translocation bearing the testis-determining.

Phenotype 3: The Infant with Ambiguous Genitalia

If an infant has a phallus that is intermediate in size between a normal penis and a normal clitoris, an aberrantly located urethral opening, and at least one impalpable gonad, the term ambiguous genitalia may be used.

The two most likely diagnoses are congenital adrenal hyperplasia (21-hydroxylase deficiency) and gonadal dysgenesis (including true hermaphroditism). Partial androgen insensitivity syndrome (PAIS) and 17beta-hydroxysteroid dehydrogenase deficiency (a defect in testosterone biosynthesis) are next in order of prevalence, followed by a group of very rare conditions (11beta-hydroxylase deficiency, 3beta-hydroxysteroid dehydrogenase deficiency, 5alpha-reductase deficiency.

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). The degree of external ambiguity is variable. 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.

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.

Defects in Steroid Hormone Biosynthesis

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.

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.

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. Deficiency of the converting enzyme 5alpha-reductase 2 results in a condition once called "pseudovaginal perineal hypospadias."

Placental Aromatase Deficiency.

Placental aromatase converts C19 androgens of fetal adrenal origin into estrogens. A deficiency in this enzyme exposes the mother and the female fetus to these androgens, and both become virilized. Development of the uterus and ovaries is unaffected. Missense mutations in the gene encoding aromatase (P450 arom) have been identified.

Partial Androgen Insensitivity Syndrome

Partial androgen insensitivity syndrome has the same phenotype as 17beta-hydroxysteroid dehydrogenase deficiency, but the hCG-stimulated ratio of androstenedione to testosterone is normal, and the levels of testosterone reached are normal or high. Serum LH may be normal or elevated. Usually, at least one gonad is palpable.

Luteinizing Hormone Receptor Gene Mutation

Leydig cell hypoplasia or agenesis occurs in a familial form. In several cases, an inactivating mutation in the gene encoding LH receptor has been demonstrated. The phenotype in XY subjects is similar to that in XY gonadal dysgenesis; the external genital genitalia are either female or ambiguous, gonads are usually not palpable, the serum gonadotropin levels are elevated.

Phenotype 4: The 46,XY Male with Persistent Mullerian Structures

Patients with the persistent mullerian duct syndrome have normal male genitalia, and the testes are usually undescended. The presence of mullerian structures (uterus and fallopian tubes) is often discovered by the surgeon at operation.

Phenotype 5: The 46,XX Female with Mullerian Agenesis

One of the causes of primary amenorrhea is mullerian agenesis. In some cases the entire mullerian tract is absent, whereas in others the agenesis affects only certain parts of the tract (such as the vagina and body of the uterus).


When an infant is born with ambiguous genitalia, the immediate problem for staff in the delivery room is what to tell the parents. The next challenge is to make a diagnosis of the underlying cause to plan management of the condition.

Removal of the Gonads to Prevent Neoplasia

Streak gonads commonly undergo malignant change. Gonadoblastoma occurs in 55% of gonads in partial XY gonadal dysgenesis and in 30% to 66% of gonads of females with complete XY gonadal dysgenesis. In a gonadoblastoma, discrete nests of germ cells are found mixed with sex cord derivatives, with prominent focal calcification.