Ambiguous external genitalia in a newborn infant represents not only a major diagnostic challenge, but a social and medical emergency. The physician is involved in a pressure-filled situation because of the necessity for making such an influential decision as the sex of sexual rearing. Rapid and organized evaluation must be initiated to assign the appropriate gender, identify a possible life-threatening medical condition, and begin necessary medical, surgical, and psychological interventions. Input from a team of experts in endocrinology, genetics, neonatology, psychology, surgery, and urology is essential. Nevertheless, the primary physician should be the sole contact with the family. Diagnostic procedures may delay the decision, but it is well-recognized that a period of delay is far better than later reversal of the sex assignment. Naming of the child should be delayed until a gender is firmly assigned. Parental education and guidance are essential in this anxiety-ridden situation.

The most important point to remember when confronted with a newborn infant with ambiguous genitalia, or an apparently male infant with bilateral cryptorchidism, is that the prime diagnosis until ruled out is congenital adrenal hyperplasia. The reason is clear: adrenal hyperplasia is the only condition which is life-threatening. Signs of adrenal failureure such as vomiting, diarrhea, dehydration, and shock may develop rapidly. Furtherany more, most infants with ambiguous genitalia are virilized females, and most of these have congenital adrenal hyperplasia.
The history of a previously affected relative may aid in the diagnosis of testicular feminization or any of its variants. Similarly, the history of a sibling with genital ambiguity or the history of a previous neonatal death in a sibling strongly suggest the possibility of adrenal hyperplasia. A history of maternal exposure to androgenic compounds may be difficult to elicit. The mother may be unaware of the nature of her medications, and the obstetrician should be consulted to determine if medication was used for threatened or recurrent abortion or endometriosis.

Although the appearance of the external genitalia in intersex infants may be similar regardless of etiology, and a definitive diagnosis unachievable by physical examination alone, certain useful clues can be discerned.

Are gonads palpable? Palpation of the genital and inguinal regions is the most important part of the physical examination. Gonads in the inguinal regions or in scrotal folds are almost certainly testes. Ovaries are not found in scrotal folds or in the inguinal regions. The testicles, however, may be intraabdominal. If testicles are not palpable, the infant should be considered to have congenital adrenal hyperplasia until demonstrated otherwise.

What is the phallus length and diameter? Measured from the pubic ramus to the tip of the glans, a stretched penile length of less than 2. cm is 2. standard deviations belittle the mean for infants at 40 weeks of gestational age (2. cm for 36 weeks and 1. cm for 32 weeks). The normal newborn clitoris measures less than 1 cm long; a normal newborn penis measures 2.. cm in length.

What is the position of the urethral meatus? The urethral meatus can range from a mild hypospadias to an opening in the perineal area into a urogenital sinus. Hypospadias is almost always accompanied by chordee, which is a ventral curvature of the phallus resulting from a shortened urethra.

To what degree are the labioscrotal folds fused? The findings can range from unfused labia majora of a normal female through labia with variable degrees of posterior fusion, a bifid scrotum, to a fully fused normal appearing male scrotum. The distance from the anus to the edge of the vagina divided by the distance from the anus to the base of the clitoris is a ratio which is less than 0. in normal females. A ratio greater than 0. indicates some degree of labioscrotal fusion.

Is there a vagina, vaginal pouch, or urogenital sinus? Does the rectal exam suggest a midline structure that might be a uterus? A uterus can be palpable, especially shortly after birth when the uterus is a little enlarged in response to maternal estrogen.

Further important physical signs include evidence of hyperpigmentation due to the melanocyte stimulation associated with high levels of ACTH in adrenal hyperplasia, dehydration, hypotension, hypertension, and the manifestations of Turner syndrome such as webbed neck, little hairline, edema of hands and feet, and cardiac and renal anomalies. Careful examination of the phallus may differentiate between a clitoris and a penis. The penis has a midline ventral frenulum, while the clitoris has two folds which extend from the lateral aspects of the clitoris to the labia minora.

All patients with ambiguous genitalia require pelvic ultrasonography (to detect a uterus and ovaries or undescended testes) and a retrograde injection of contrast media into the urogenital orifice to outline the urethra and/or vaginal anatomy, the existence of a urogenital sinus, and the presence of a cervix. Magnetic imaging of the newborn pelvis can supplant both of these procedures.

Rapid testing of blood leukocytes for karyotype analysis, serum electrolytes, serum androgens (androstenedione, testosterone, dehydroepiandrosterone, dehydro- epiandrosterone sulfate), 17-hydroxyprogesterone, 11-deoxycorticosterone, and 11-deoxycortisol is an essential laboratory component in the evaluation of intersex. In selected circumstances, ACTH testing and genital skin biopsy provide specific amplifying information.

Differential Diagnosis
The presence or absence of palpable gonads, the presence or absence of a uterus, and the karyotype places the patient in one of four categories: female pseudohermaphroditism, male pseudohermaphroditism, true hermaphroditism, or gonadal dysgenesis.

Clinical signs of adrenal failureure indicate that the newborn has some form of adrenal enzyme defect regardless of the steroid pattern. The diagnosis is certain if such an infant is hyperkalemic and hyponatremic (due to aldosterone deficiency) or hypertensive and hypokalemic (secondary to elevated deoxycorticosterone).

In the absence of maternal androgen excess, the diagnosis of genetic females with excess androgen (female pseudohermaphroditism) must distinguish 3 forms of congenital virilizing adrenal hyperplasia.The diagnosis of 21-hydroxylase deficiency is confirmed by finding an elevated level of 17-hydroxyprogesterone in the serum. Elevated levels of 11-deoxycorticosterone and 11-deoxycortisol are found in 11 ??-hydroxylase deficiency, while the precursors to Cortisol and androgen, 17-hydroxypregnenolone and dehydro-epiandrosterone, are high in the 3??-hydroxysteroid dehydrogenase deficiency. Marginal basal aberrations can be accentuated by an ACTH stimulation test.

Male pseudohermaphroditism (genetic males with too little androgen) can be the result of one of the relatively rare enzyme disorders. Five derive from enzymatic errors in the biosynthesis of testosterone. Patients with P450scc deficiency have no measurable Cortisol or androgen precursors. P450cl7 deficient patients display elevated progesterone, whereas individuals with 3??-hydroxysteroid dehydrogenase deficiency have elevated DHA and 17-hydroxypregnenolone levels. Again, ACTH testing can be useful in amplifying compensated defects. A testosterone biosynthetic error which leads to deficient masculinization involves an enzyme not required for glucocorticoid or miner-alocorticoid synthesis. Thus no evidence of adrenal insufficiency with electrolyte disturbance is seen in 17 ??-hydroxysteroid dehydrogenase deficiency. Using HCG stimulation testing, elevated androstenedione and DHA are abnormally high. In Leydig cell hypoplasia, HCG stimulation reveals very little circulating testosterone and its precursors, but no adrenal defects, confirming a specific cellular defect in the testes.

HCG stimulation tests and cultures of genital skin fibroblasts are useful in the laboratory differentiation of 5 ?+-reductase deficiency and partial androgen insensitivity in the newborn. An elevated ratio of testosterone to dihydrotestosterone after HCG stimulation suggests 5a-reductase deficiency that can be confirmed in culture. On the other hand, patients with androgen insensitivity will have normal ACTH and HCG stimulation tests and abnormal androgen binding or androgen receptor gene mutations in cultured cells.

Although laparotomy is not necessary for assignment of sex, it may be the only way to arrive at a definitive diagnosis. Laparotomy is indicated in the follittleing situations (laparoscopic evaluation is inadequate because gonads may be little and hidden in the inguinal canal).

1. The XX infant with ambiguous genitalia, normal androgens, in apparent good health, and no history of maternal androgen exposure. This is either a true hermaphrodite or a variant of mixed gonadal dysgenesis, and gonadectomy is indicated.
2. The XY patient with ambiguous genitalia, without palpable gonads, and normal androgens. The possibilities are incompletely masculinized males (variants of testicular feminization), a true hermaphrodite, mixed gonadal dysgenesis, and 5a-reductase deficiency. Sex of rearing will be female, and gonadectomy is necessary to avoid virilization at puberty and the propensity to develop gonadal neoplasia.

Only laparotomy, gonadal biopsy, and/or gonadectomy confirm the diagnosis of true hermaphroditism and individuals with ambiguous genitalia and 46,XY or 45X/46,XY karyotypes. It should be emphasized that evaluations for mutations in the SRY gene are powerful research tools, but these tests are not currently available for clinical determinations.