Sexual Differentiation (Chapter 576)

In normal differentiation, the final form of all sexual structures is consistent with normal sex chromosomes (either XX or XY). A 46,XX complement of chromosomes as well as genetic factors such as DAX1 and the signaling molecule WNT-4 are necessary for the development of normal ovaries. Development of the male phenotype is even more complex. It requires a Y chromosome and, specifically, an intact SRY gene, which, in association with other genes such as SOX9, SF1, and WT1 and others (Chapter 576), directs the undifferentiated gonad to become a testis. Aberrant recombinations may result in X chromosomes carrying SRY, resulting in XX males, or Y chromosomes that have lost SRY, resulting in XY females.

Antimüllerian hormone (AMH) causes the müllerian ducts to regress; in its absence, they persist as the uterus, fallopian tubes, cervix, and upper vagina. AMH activation in the testes may require the SF1 gene for activation. By about 8 wk of gestation, the Leydig cells of the testis begin to produce testosterone. During this critical period of male differentiation, testosterone secretion is stimulated by placental human chorionic gonadotropin (hCG), which peaks at 8-12 wk. In the latter half of pregnancy, lower levels of testosterone are maintained by luteinizing hormone secreted by the fetal pituitary. Testosterone produced locally initiates virilization of the ipsilateral Wolffian duct into the epididymis, vas deferens, and seminal vesicle. Development of the external genitals also requires dihydrotestosterone (DHT), an active metabolite of testosterone. DHT produced from circulating testosterone is necessary to fuse the genital folds to form the penis and scrotum. A functional androgen receptor, produced by an X-linked gene, is required for testosterone and DHT to induce these virilizing changes.

In the XX fetus with normal long and short arms of the X chromosome, the bipotential gonad develops into an ovary by about the 10th-11th wk. This occurs only in the absence of SRY, testosterone, and AMH and requires a normal gene in the DSS locus DAX1, and the WNT-4 molecule. A female phenotype develops in the absence of fetal gonads. However, the male phenotype development requires androgen production and action. Estrogen is unnecessary for normal prenatal sexual differentiation, as demonstrated by 46,XX patients with aromatase deficiency and by mice without estradiol receptors.

Chromosomal aberrations may result in ambiguity of the external genitalia. Conditions of aberrant sex differentiation may also occur with the XX or XY genotype. The appropriate term for what was previously called intersex is disorders of sex development (DSD). This term defines a condition “in which development of chromosomal, gonadal or anatomical sex is atypical.” It is becoming more preferable to use the term “atypical genitalia” rather than “ambiguous genitalia.” Comparison with the previous terms and a new etiologic classification are seen in Tables 582-1 and 582-2. Some of the genes involved in disorders of sex development are listed in Table 576-1.

Table 582-1 REVISED NOMENCLATURE

From Lee PA, Houk CP, Ahmed SF, et al: Consensus statement on management of intersex disorders, Pediatrics 118:e488–e500, 2006.

The definition of atypical or ambiguous genitalia, in a broad sense, is any case in which the external genitalia do not appear completely male or completely female. Although there are standards for genital size dimensions, variations in size of these structures do not always constitute ambiguity.

Development of the external genitalia begins with the potential to be either male or female (Fig. 582-1). Virilization of a female, the most common form of DSD, results in varying phenotypes (Fig. 582-2), which start from the basic genital appearances of the embryo (see Fig. 582-1).

Figure 582-1 Schematic demonstration of differentiation of normal male and female genitalia during embryogenesis.

(From Zitelli BJ, Davis HW: Atlas of pediatric physical diagnosis, ed 4, St Louis, 2002, Mosby, p 328.)

Figure 582-2 Examples of atypical genitalia. These cases include ovotesticular disorder of sexual development (A) and congenital virilizing adrenal hyperplasia (B-E). (B-D, Courtesy of D. Becker, MD, Pittsburgh.)

(From Zitelli BJ, Davis HW: Atlas of pediatric physical diagnosis, ed 4, St Louis, 2002, Mosby, p 329.)

Diagnostic Approach to the Patient with Atypical or Ambiguous Genitalia

The appearance of the external genitalia is rarely diagnostic of a particular disorder, and thus does not often allow distinction among the various forms of DSD. The most common forms of 46,XX DSD are virilizing forms of congenital adrenal hyperplasia (CAH). It is important to note that in 46,XY DSD, the specific diagnosis is not found in up to 50% of cases. At 1 center with a large experience, the etiologies of DSD in 250 patients over 25 yr were compiled. The 6 most common diagnoses accounted for 50% of the cases. These included virilizing CAH (14%), androgen insensitivity syndrome (10%), mixed gonadal dysgenesis (8%), clitoral/labial anomalies (7%), hypogonadotropic hypogonadism (6%), and 46,XY small-for-gestational age males with hypospadias (6%).

This potential source of error in diagnosis and management emphasizes the need for careful diagnostic evaluation including biochemical characterization of possible steroidogenic enzymatic defects in each patient with genital ambiguity. The parents need counseling about the complex nature of the baby’s condition, and guidance as to how to deal with their well-meaning but curious friends and family members. The evaluation and management should be carried out by a multidisciplinary team of experts that include pediatric endocrinology, pediatric surgery/urology, pediatric radiology, newborn medicine, genetics, and psychology. Once the sex of rearing has been agreed on by the family and team, treatment can be organized. Genetic counseling should be offered when the specific diagnosis is established.

After a complete history and physical exam, the common diagnostic approach includes multiple steps, described in the following outline. These steps are usually performed simultaneously rather than waiting for results of 1 test prior to performing another, due to the sensitive and sometimes urgent nature of the condition. Careful attention to the presence of physical features other than the genitalia is crucial, to determine if a diagnosis of a particular multisystem syndrome is possible. These are described in more detail in Chapters 582.1, 582.2, and 582.3. A summary of many features of commonly encountered causes of DSD is provided in Table 582-3.

Diagnostic tests include the following: