Taylor_Speroff's Clinical Gynecologic Endocrinology and Infe

Chapter 8 • Normal and Abnormal Sexual Development 265

46,XX Disorders of Sexual Development DSD in chromosomal females can result from abnormalities in gonadal development, but most are caused by androgen excess, which may be of fetal, fetoplacental, or maternal ori gin. Excess fetal androgen production results from steroido genic enzyme deficiencies causing CAH. Androgen excess of fetoplacental origin results from enzyme deficiencies involving both the fetal adrenal and the placenta. Maternal androgen excess can result from the ingestion of drugs hav ing androgenic properties and from disorders causing gesta tional hyperandrogenism. Disorders of Gonadal (Ovarian) Development Rarely, 46,XX DSD can result from abnormalities of gonadal development, which include ovotesticular DSD (true her maphroditism), testicular DSD (46,XX sex reversal), and gonadal dysgenesis. Ovotesticular DSD previously was called true hermaphrodit ism. 115 Hermaphroditus, the Greek god with bisexual attributes, was the child of Hermes—the god of athletics, secrets, and occult philosophy—and Aphrodite, the goddess of love. The bisex ual theme was immortalized in Greek and Roman sculptures depicting a woman with male external genitalia. Pliny (23–79 a.d.) was the first to apply the term hermaphrodite to humans, offering a description in his massive work, Historia Naturalis . Ovotesticular DSD is a rare condition characterized by mixed ovarian and testicular tissue, which may include bilateral ovotestes or an ovotestis and a contralateral ovary or testis. The disorder is described here because the major ity of patients have a 46,XX karyotype. However, because 7% of patients with ovotesticular DSD have a 46,XY karyotype and 10–40% exhibit chromosomal mosaicism, 116 the disor der also must be listed among the causes of 46,XY and sex chromosome disorders of sexual development. Whereas gonads containing testicular tissue are observed most frequently on the right, normal ovaries are observed most often on the left. 116 Usually, both müllerian and wolffian internal genital structures are present, and as could be pre dicted, internal genital structures correspond with the adja cent gonad. Whereas most have a vagina, the uterus can be normal and functional, hypoplastic, vestigial, or altogether absent. 116,117 External genital development reflects the level of androgen production and exposure, and the phenotype can range widely, from ambiguous genitalia to isolated hypospa dias. Most are virilized sufficiently to allow male sex assign ment, but three-fourths develop gynecomastia and half menstruate after puberty. The genetics and pathophysiology of ovotesticular DSD are not well established. Mechanisms that might explain the testicular development include the translocation of testis-determining genes from the Y to the X chromo some or an autosome and autosomal dominant mutations Ovotesticular Disorder of Sexual Development (True Hermaphroditism)

that promote testis development in the absence of a Y chromosome. 118 In one individual, the condition has been associated with an inactivating mutation in the RSPO1 gene, 119 which is located on chromosome 1p34.2–3.

Testicular Disorder of Sexual Development (46,XX Sex Reversal)

Testicular DSD is a rare “sex reversal” syndrome in which the chromosomal sex (46,XX) is not consistent with the gonadal sex (testes). The disorder was first described by de la Chapelle in 1964 120 and can be divided into two types, SRY positive and SRY negative. Approximately 90% of cases result from abnormal recombination between the distal portions of the short arms of the X and Y chromosomes and transfer of SRY from the Y to the X chromosome during male mei osis; in 10% of cases, SRY cannot be detected. 121 In most SRY -negative patients, the mechanism causing testis devel opment cannot be determined. 121–124 Although some patients with SRY -positive testicular DSD have ambiguous genitalia, which may result from preferential inactivation of the SRY -bearing X chromosome, 125 the large majority are sterile males with normal genital development, a normal male hair pattern, and short stature. Consequently, unless they have cryptorchid testes, most are not recognized until after puberty, when they may present with hypogonadism, gynecomastia, and/or infertility. 121 In contrast, SRY -negative XX males usually have ambiguous genitalia and often develop gynecomastia or fail to masculinize fully after puberty. 121–124 Rarely, they may exhibit occult gonadal mosaicism for SRY . 126 In some, the phenotype has been linked to a duplication of sequences on chromosome 17q, including the SOX9 gene, which acts downstream of SRY in the testis-determining path way. 32,127 However, in most patients with SRY -negative testicular DSD, the cause remains unclear. In theory, XX male sex reversal might result from an inactivating mutation or deletion in genes encoding factors that inhibit testis development, but there is no direct evidence that they are a cause of testicular DSD. 122 Gonadal Dysgenesis Some individuals with primary amenorrhea, hypergo nadotropic hypogonadism, and gonadal dysgenesis (streak gonads) have a normal 46,XX karyotype, providing indirect evidence that autosomal genes also play a critical role in ovarian differentiation. Affected women are normal in stat ure and, in most cases, have no apparent somatic anomalies. A wide variety of candidate genes have been identified, pri marily via experiments involving murine knockout models, including several that encode DNA- and RNA-binding pro teins and transcription factors expressed during oogenesis. 128 Androgen Excess—Fetal Origin (Congenital Adrenal Hyperplasia) Virilizing CAH is a genetic disorder caused by enzyme defects in adrenal cortisol biosynthesis. More than 90% of cases result from a deficiency in the enzyme 21-hydroxylase. 129–131

II

Copyright © 2019 Wolters Kluwer, Inc. Unauthorized reproduction of the content is prohibited.