General Medical Information

Workup of Newborns With Ambiguous External Genitalia

Claude J. Migeon and Gary D. Berkovitz

As already stated, it is an emergency to determine the etiology of the ambiguous genitalia because it will help in the decision making as far as the sex of rearing is concerned. It also can be a medical emergency as, in some cases, the mutation responsible for the abnormal genitalia results in life-threatening symptoms. Following is an example of a schedule for tests that need to be ordered: day 1, karyotype (fluorescent Y chromosome); day 2, plasma testosterone, dihydrotestosterone, and androstenedione; day 3, plasma progesterone, 17-hydroxyprogesterone, 17-hydroxypregnenolone, and androstenedione; day 4, sonogram (gonads-uterus), genitogram with or without intravenous pyelogram; and day 6, repeat plasma 17-hydroxyprogesterone and androstenedione.

At least once a day, it is necessary to check the levels of serum electrolytes and blood glucose (dextro-stick). The infant also must be weighed carefully every day.

The results of these tests will help in determining the etiology of the ambiguous genitalia. The importance of the karyotype is self-evident. Although the search for a fluorescent Y chromosome is of interest, it is important to remember that the locus of the fluorescence is on the long arm of that chromosome, whereas the gene that initiates testicular formation (SRY) is located on the short arm. A buccal smear is not sufficient as a technique for determining the sex chromosome complement and should not be used.

The study of androgens (androstenedione, testosterone, and dihydrotestosterone) must be done on a single blood sample to permit determination of the ratios of androstenedione to testosterone and of testosterone to dihydrotestosterone. Abnormally elevated ratios would be evidence of a deficiency in 17-ketosteroid reductase and 5a-steroid reductase, respectively. This investigation is timed for day 2 of life, because testicular androgen levels tend to decrease on days 3 to 8, before returning later to values of 150 to 250 ng/dL for testosterone.

The concentrations of 17-hydroxyprogesterone and progesterone normally are elevated in cord blood and shortly after birth. However, by day 3 of life they have reached levels that make possible the differentiation of normal values from those observed in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. This pattern also applies to the levels of androstenedione. On occasion, it is appropriate to repeat the assays of various steroids if the original results are not conclusive.

Sonogram and genitogram permit determination of the nature and localization of the internal ducts and their relationship to the urethra. In a markedly masculinized female, the vagina may open in the urethra via a narrow canal. In undermasculinized males, a utricular-vaginal pouch can be observed, opening in the urethra but ending blindly, without cervix or uterus.

Deficiency of some of the enzymes necessary for the biosynthesis of cortisol and aldosterone (21-hydroxylase, 3b-hydroxysteroid dehydrogenase isomerase, side chain cleavage) results in abnormalities of the external genitalia. In such cases, an acute adrenal crisis with hyponatremic, hyperkalemic acidosis, and hypoglycemia can develop, usually between days 2 and 6 of life. Hence, adequate monitoring of serum electrolytes and glucose are of great importance. Dehydration and marked weight loss also are symptoms of the adrenal crisis. A lack of adequate therapy may have catastrophic results.