CHAPTER 107

Disorders of Sexual Differentiation

Jennifer K. Yee, MD, and Catherine S. Mao, MD

Disorders of sexual differentiation (DSDs) in newborns can result in ambiguous genitalia and are classified according to chromosomal status and gonads present. This standard classification, using newer nomenclature with previously used nomenclature in parentheses, includes 46,XX DSD (ie, female pseudohermaphroditism), 46,XY DSD (ie, male pseudohermaphroditism), ovotesticular DSD (ie, true hermaphroditism), and 46,XX testicular DSD or 46,XY gonadal dysgenesis (ie, complete or mixed gonadal dysgenesis). Gonadal dysgenesis in 45,X and 46,XX individuals does not present with ambiguous genitalia but is also classified as a DSD.

A multidisciplinary team should be involved in the care of the newborn with a DSD. In addition to the general pediatrician, significant members of the team include nurses, social workers, neonatologists, pediatric endocrinologists, geneticists, and surgeons. The role of the primary care physician cannot be underestimated, however, because this professional is always involved in the initial evaluation of the newborn and often has an established relationship with the family.

Epidemiology

The prevalence of ambiguous genitalia in newborns is approximately 1 in 3,000 to 4,000 live births. The 46,XX DSD is characterized by female chromosomes (46,XX), normal ovaries and müllerian structures, and virilized external genitalia. The most common DSD—46,XX DSD—is most often caused by congenital adrenal hyperplasia (CAH). Neonatal screening studies suggest that the incidence of CAH is 1 in 5,000 to 15,000 live births per year.

The 46,XY DSD occurs in genetic males (46,XY) who have testes but with insufficient masculinization of the external genitalia. This disorder most commonly results from androgen insensitivity. Ovotesticular DSD is a rare condition in which ovarian and testicular tissues are present. Seventy percent to 80% of affected individuals have the 46,XX karyotype, and the morphology of the external genitalia varies widely.

The 46,XY gonadal dysgenesis is characterized by ambiguous genitalia or a female phenotype with a normal XY karyotype. The affected neonate may have a specific gene abnormality that results in abnormal testicular development and often streak gonads. Reports indicate that this condition is the second most common form of ambiguous genitalia. The affected newborn with chromosomal mosaicism (45,X/46,XY) is considered to have mixed gonadal dysgenesis.

Clinical Presentation

Variability in the phenotypic and clinical presentation of these disorders is considerable (Box 107.1). The newborn with DSD with ambiguous genitalia may have an enlarged clitoris or small phallus and varying degrees of labioscrotal fusion. Signs of virilization in the female newborn might include hyperpigmented labia and presence of labial rugae. Other findings suggestive of 46,XX DSD are perineal hypospadias or an inguinal hernia. More dramatic presentations, such as severe dehydration and shock in a neonate, are associated with CAH of the salt-wasting form. Females with gonadal dysgenesis often present in adolescence with primary amenorrhea (see Chapter 61). Turner syndrome (45,XO) is a common cause of gonadal dysgenesis and may present with additional clinical features; 46,XX “pure” gonadal dysgenesis is a distinct entity.

Pathophysiology

To appropriately evaluate and interpret laboratory results of the neonate with ambiguous genitalia, it is important to understand the physiology of sexual differentiation and how deviations from this process result in DSD.

Normal Sexual Differentiation

Before an embryo reaches 6 weeks, germ cells migrate from the yolk sac into the undifferentiated bilateral gonads. Both wolffian and müllerian duct systems are present, and the embryonic gonads of males and females are indistinguishable at this time.

If a Y chromosome is present, a testes-determining factor known as sex-determining region Y (SRY) induces differentiation of these gonads into testes by stimulating SOX9 (SRY-related gene) expression in the gonads, thus blocking female development. This process involves the formation of seminiferous tubules that surround the germ cells. Leydig cells begin to produce testosterone, which in turn acts on the wolffian duct to result in male internal genitalia: vas deferens, epididymis, and seminal vesicles. Concurrently, SOX9 acts with steroidogenic factor 1, resulting in regression of the müllerian ducts secondary to Sertoli cell production of anti-müllerian hormone, also known as müllerian-inhibiting substance. The formation of normal male external genitalia is dependent on the conversion of testosterone to dihydrotestosterone (DHT) via 5- -reductase. Dihydrotestosterone then combines with a specific androgen receptor, which allows formation of the phallus and scrotum from the previously undifferentiated external genitalia. The process primarily involves growth and fusion. Later in gestation, the testes migrate into the scrotum.

The development of undifferentiated gonads into female organs is dependent on the absence of the Y chromosome and the presence of 2 intact and normal functioning X chromosomes. Because androgens are not produced and anti-müllerian hormone is not present, the wolffian duct degenerates and the müllerian duct develops into the internal female structures: fallopian tubes, uterus, and upper vagina. Fusion of undifferentiated external genitalia does not occur in the absence of DHT; thus, the external genitalia develops into the labia, and the genital tubercle becomes the clitoris. Female differentiation was previously believed to be the default development in the absence of SRY; however, recent studies support the existence of female determining factors (ie, R-spondin1 and Wnt signaling molecule Wnt4).

Disorders of Sexual Differentiation

Congenital adrenal hyperplasia is the most common cause of virilization of the female and is an autosomal recessively inherited defect. Congenital adrenal hyperplasia is the result of an enzymatic deficiency in the pathway for synthesis of cortisol and aldosterone from cholesterol. The most common of these enzymatic defects is 21- -hydroxylase deficiency. Other less common defects are 11-β-hydroxylase deficiency and 3-β-hydroxysteroid dehydrogenase deficiency. Lipoid adrenal hyperplasia results from a defect in the steroidogenic acute regulatory (StAR) protein enzyme that transports cholesterol across the mitochondrial membrane for steroid synthesis. A rare form of CAH is cytochrome P-450 oxidoreductase deficiency, which can be associated with Antley Bixler syndrome. Prenatally, circulating levels of androgens are abnormally high from the overproduction of precursors in the steroid synthesis pathways. As a result, the external genitalia of the fetus, which are controlled by androgens, are virilized in the female. Internal female organs, however, are normal because their development is not influenced by androgens. Males with the common forms of CAH (21- -hydroxylase and 11-β-hydroxylase deficiency) may exhibit hyperpigmentation and increased rugosity but otherwise have normal external genitalia.

Approximately two-thirds of patients with classic CAH resulting from 21- -hydroxylase deficiency have the salt-wasting form. Because of low levels of aldosterone, sodium resorption in the renal tubules is reduced, resulting in hyponatremia and hyperkalemia. If this salt-wasting condition goes undiagnosed and unmanaged, shock and death may result in the first few weeks after birth. Newborn screening programs are currently in place in all 50 US states. These programs screen for elevated 17 -hydroxyprogesterone, targeting identification of patients with 21- -hydroxylase deficiency, and are less sensitive for detection of neonates with 11-β-hydroxylase deficiency and 3-β-hydroxysteroid dehydrogenase deficiency.

The 46,XY DSD is secondary to insufficient testosterone production or insensitivity at the cellular level. Androgen insensitivity, the most common cause of this disorder, is the result of an abnormality or a reduction in the number of androgen receptors. Not all affected individuals present with ambiguous genitalia at birth because the spectrum of sensitivity is broad. If the androgen receptor is completely nonfunctional or absent, the external genitalia are those of a normal female (ie, complete androgen insensitivity syndrome). In the setting of partial function of the androgen receptor, genital ambiguity occurs. This is an X-linked condition that affects only 46,XY individuals; however, 46,XX females are carriers and pass the mutation to their offspring.

Other causes of 46,XY DSD are inadequate testosterone production secondary to low levels of fetal gonadotropins; defects in testosterone synthesis from enzyme deficiencies or disruption of electron transport; failure to convert testosterone to DHT as a result of 5- -reductase deficiency; deficient müllerian duct-inhibiting substance, which can be autosomal recessive or X-linked recessive; and intrauterine loss of both testes secondary to torsion or another prenatal event. Causes of testosterone deficiency resulting in 46,XY DSD include CAH caused by defects of StAR, P-450 side-chain cleavage, 3-β-hydroxysteroid dehydrogenase, 17- -hydroxylase, and P-450 oxidoreductase.

Although SRY is considered to be the sex-determining region, defects in SRY explain only approximately 15% of XY gonadal dysgenesis. A loss of function mutation in SOX9 results in camptomelic dysplasia with XY sex reversal. More recently, an abnormality of a gonad-specific regulatory region of SOX9 resulted in isolated XY gonadal dysgenesis. Steroidogenic factor 1 mutations have been estimated to account for up to 13% of cases of XY gonadal dysgenesis.

Although most causes of ambiguous genitalia are related to chromosomal abnormalities and inherited enzymatic defects, exogenous sources of hormones can affect the differentiation of sexual organs. In most cases, the effect is minimal and no ambiguity occurs. Masculinized female external genitalia can occur, however, depending on the timing and duration of prenatal exposure to androgens or other virilizing drugs. Currently, the most commonly used androgens are likely anabolic steroids. A neonate may even be exposed prenatally through transdermal passage to the mother from a family member using androgen creams. An adrenal tumor or poorly controlled CAH in the mother will also result in virilization of the female fetus. The progestin in birth control pills does not have sufficient androgen action to cause a problem.

Differential Diagnosis

The differential diagnosis of ambiguous genitalia depends on the classification of the DSD (Table 107.1). Some causes of this condition can be life-threatening and must be recognized immediately (eg, salt-wasting CAH).

Evaluation

History

The general obstetric history should be reviewed, although it may not be helpful in all cases. Likely the most important source of information on family history can be derived from family pedigrees (Box 107.2). The mother of the affected newborn should be interviewed thoroughly for any clinical findings that might suggest her as the source of androgens. Undiagnosed chromosomal disorders, consanguinity, and recurrent medical conditions may be established or inferred from the family background.

Table 107.1. Classification and Causes of Disorders of Sexual Differentiation in the Newborn

Abbreviation: DSD, disorders of sexual differentiation.

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