Disorders of Sex Development

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Chapter 582 Disorders of Sex Development

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

PREVIOUS CURRENTLY ACCEPTED
Intersex Disorders of sex development (DSD)
Male pseudohermaphrodite 46,XY DSD
Undervirilization of an XY male 46,XY DSD
Undermasculinization of an XY male 46,XY DSD
46,XY intersex 46,XY DSD
Female pseudohermaphrodite 46,XX DSD
Overvirilization of an XX female 46,XX DSD
Masculinization of an XX female 46,XX DSD
46,XX intersex 46,XX DSD
True hermaphrodite Ovotesticular DSD
Gonadal intersex Ovotesticular DSD
XX male or XX sex reversal 46,XX testicular DSD
XY sex reversal 46,XY complete gonadal dysgenesis

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

Table 582-2 ETIOLOGIC CLASSIFICATION OF DISORDERS OF SEX DEVELOPMENT (DSD)

46,XX-DSD

Androgen Exposure

Disorder of Ovarian Development

Undetermined Origin

Associated with genitourinary and gastrointestinal tract defects

46,XY DSD

Defects in Testicular Development

Deficiency of Testicular Hormones

Defect in Androgen Action

Ovotesticular DSD

Sex Chromosome DSD

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).

image

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.)

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:

582.1 46,XX DSD

In this condition, the genotype is XX and the gonads are ovaries, but the external genitalia are virilized. Because there is no significant AMH production—the gonads are ovaries—the uterus, fallopian tubes, and cervix develop. The varieties and causes of this condition are relatively few. Most instances result from exposure of the female fetus to excessive exogenous or endogenous androgens during intrauterine life. The changes consist principally of virilization of the external genitalia (clitoral hypertrophy and labioscrotal fusion).

Congenital Adrenal Hyperplasia (Chapter 570.1)

This is the most common cause of genital ambiguity and of 46,XX DSD. Females with the 21-hydroxylase and 11-hydroxylase defects are the most highly virilized, although minimal virilization also occurs with the type II 3β-hydroxysteroid dehydrogenase defect (see Fig. 582-1). Salt losers tend to have greater degrees of virilization than do non–salt-losing patients. Masculinization may be so intense that a complete penile urethra results, and the condition may mimic a male with bilateral cryptorchidism.

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