The etiology underlying genital ambiguity in newborns impacts several aspects of management including recommendations for sex of rearing. The importance of making this recommendation early, along with the possibility for metabolic disorders that can be life threatening, warrant a thorough evaluation as early in life as possible.
A comprehensive assessment of an affected newborn is very important, as ambiguous genitalia can occur in conjunction with several other congenital malformations. It is necessary to look for signs of dehydration with vomiting and diarrhea, as these are symptoms of a salt-losing crisis. A careful examination of the external genitalia must also be performed. A genital exam must include a measure of stretched phallic length, evaluation of the quality of the corpora, and inspection of the labia, labio-scrotal folds or scrotum. The position of the urethral opening (and vaginal opening if applicable) should be documented, as well as the presence and location of palpable gonads.
Serum electrolytes and glucose levels should be monitored daily as cortisol deficiency can manifest as hypoglycemia in newborns affected by CAH. Body weight should also be monitored as excessive weight loss may indicate pathological dehydration.
It is crucial to obtain a karyotype as soon after birth as possible (Figure 1). Laboratories should be informed to look for sex chromosome mosaicism and deletions. Studies of the fluorescence of the long arm of the Y chromosome and hybridization with an SRY gene probe on the short arm of the Y chromosome are also helpful.
Hormone studies are classified according to the following categories; gonadotropins (LH, FSH), androgens and androgen precursors (17-hydroxypregnenolone, 17-hydroxyprogesterone, androstenedione, testosterone, dihydrotestosterone), adrenal steroids (cortisol, aldosterone, and their precursors) and Müllerian inhibiting substance (MIS) (39, 40). The following schedule for hormone studies is suggested:
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At Day 1 obtain a karyotype.
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At Day 2 of life, measure plasma androstenedione, testosterone and dihydrotestosterone. These androgens must be measured from a single blood sample so that the ratios of androstenedione/testosterone and testosterone/DHT can be calculated.
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At Day 3 or 4 of life measure plasma 17-hydroxyprogesterone, 17-hydroxypregnenolone and progesterone.
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At Day 6 or 7 of life measure plasma MIS and obtain white cells for DNA studies such as androgen receptor gene mutations.
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At Day 8 repeat androstenedione, testosterone, DHT, and 17-hydroxyprogesterone measures.
A sonogram or an MRI can be helpful in identifying both the type and extent of internal sex organ development. Imaging can also detect abnormalities of the urinary tract (kidney, ureters, bladder) that occur in individuals affected by DSD. An MRI may be better able to identify Müllerian structures (uterus, fallopian tubes, upper portion of the vagina) than a sonogram, and can also be useful for localizing the gonads. A genitogram is also needed for visualization of the urinary tract, and to determine its position in relation to the vagina or vagino-utricular pouch, when present. It is helpful to establish the presence and size of the vagina or utricular pouch. Information obtained from a genitogram is particularly useful for surgical construction of the genitalia when needed or elected.
As our knowledge of the genes involved in sex differentiation increases, and as molecular technologies develop, it will be possible to determine specific genetic etiologies underlying DSDs in the future. Some genetic investigations, such as detection of AR gene mutations, are already available clinically (49). Other techniques are employed for research purposes but are not yet available for diagnostic purposes. Such information will prove to be increasingly important for the management of patients and the family planning of their parents.