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Chapter 532: Disorders of Sexual Development

Bonnie McCann-Crosby; Melvin M. Grumbach; Lefkothea P. Karaviti

INTRODUCTION

Disorders of sexual development (DSD) are a group of congenital conditions in which there is abnormal development of chromosomal, gonadal, or anatomic sex. DSDs can be divided into 3 broad categories: (1) 46,XX DSD, (2) 46,XY DSD, and (3) sex chromosome DSD. Table 532-1 presents the classification of DSD for clinical use. The clinical presentation, management approach, and considerations for sex assignment are discussed in the final section of this chapter.

TABLE 532-1CLASSIFICATION OF DISORDERS OF SEXUAL DEVELOPMENT (DSD)
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TABLE 532-1CLASSIFICATION OF DISORDERS OF SEXUAL DEVELOPMENT (DSD)

46,XX DSD–Disorders of Ovarian Development

XX ovotesticular DSD

46,XX testicular DSD (SRY gene translocation, duplicate SOX9)

46,XX gonadal dysgenesis

46,XX DSD–Androgen Excess

Congenital adrenal hyperplasia (21-hydroxylase deficiency, 11-hydroxylase deficiency, 3β-hydroxysteroid dehydrogenase deficiency)

Aromatase deficiency

P450 oxidoreductase deficiency

Maternal source (ingestion of progestins or androgens, virilizing adrenocortical tumors, ovarian tumors, luteomas)

46,XY DSD–Disorders of Testicular Development

Complete gonadal dysgenesis (Sywer syndrome)

Partial gonadal dysgenesis (including camptomelic dysplasia, Denys-Drash, Frasier syndrome)

Gonadal regression or vanishing testes syndrome

XY ovotesticular DSD

46,XY DSD–Disorders of Androgen Synthesis or Action

Complete or partial androgen insensitivity syndrome

Testosterone biosynthesis enzyme defects: 7-dehydrocholesterol reductase deficiency–Smith-Lemli-Opitz syndrome, StAR deficiency, P450scc deficiency, 3β-hydroxysteroid dehydrogenase Type II deficiency, 17α-hydroxylase deficiency, 17,20-lyase deficiency, type III 17β-hydroxysteroid dehydrogenase deficiency

Persistent Müllerian duct syndrome

Leydig cell aplasia or hypoplasia

5α-Reductase deficiency

Environmental factors

Syndromic associations

Sex Chromosome DSD

Turner syndrome (45,X)

Klinefelter syndrome (47,XXY)

Mosaic karyotypes including 45,X/46,XY, 46,XX/46,XY

46,XX DISORDERS OF SEXUAL DEVELOPMENT

Persons with 46,XX DSD have a 46,XX karyotype and can present with variable degrees of genital ambiguity of the urogenital sinus and external genitalia. The disorders are subdivided into those of gonadal (ovarian) development and androgen excess, as shown in Table 532-1.

DISORDERS OF GONADAL (OVARIAN) DEVELOPMENT

Ovotesticular DSD

This is a rare condition in which an individual has the presence of both ovarian and testicular tissue. Patients can present with a wide range of genital ambiguities as well as a combination of both Wolffian and Müllerian structures depending on the degree of functioning testicular tissue. Only a small proportion of children with XX ovotesticular disorder of sexual development are SRY (sex determinining region on the Y chromosome) positive. The majority of patients with ovotesticular DSD have a 46,XX karyotype; however, other karyotypes such as 46,XY and mosaics such as 46,XX/46,XY have also been associated. SRY translocation in XX individuals can lead to ovotesticular DSD; however, in many cases, the specific genes responsible for development of an ovotestes have not been or cannot be identified.

46,XX Testicular DSD

This is a rare condition in which both gonads develop as testes without the presence of ovarian tissue or Müllerian structures in a 46,XX individual. Most cases are caused ...

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