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Chapter 8 • Normal and Abnormal Sexual Development 277

patients, the disorder results from an inactivating muta tion in the SRY gene, but in most, no cause can be identi fied. 340 Mutations in other genes involved in the regulation of SRY expression or encoding important downstream elements in the testis-determining pathway have been implicated. 341–343 Patients with Swyer syndrome generally present after the expected time of puberty with delayed sexual maturation, primary amenorrhea, normal pubic hair, and normal female internal and external genital anatomy. Evaluation reveals hypergonadotropic hypogonadism, prompting a karyotype that establishes the diagnosis. Gonadectomy is indicated soon after diagnosis due the significant risk for development of germ cell tumors in occult testicular elements (20–30%). 344 Sex of assignment and rearing and gender identify is unequivocally female, and no specific treatment is required other than estrogen therapy to induce breast development and, subsequently, estrogen and progestin therapy (cyclic or combined) to maintain sexual maturation. Pregnancy can be achieved with IVF using donor oocytes and has not been associated with any specific risks or complications. 345

Partial Gonadal Dysgenesis Partial gonadal dysgenesis describes a group of disorders resulting from a wide assortment of genetic mutations caus ing abnormal gonadal development and function. In affected patients, müllerian structures may be present or absent, the external genitalia may be female, ambiguous, or male, and the phenotype can include developmental abnormalities outside of the reproductive tract. The wide variations in phenotype reflect the many different actions of the gene products, which are involved in the regulation of SRY expression, müllerian regression, testis differentiation, and developmental pattern ing. Examples include single-gene disorders involving WT1 , SF1 , SRY , SOX9 , DHH (an intercellular signaling molecule having an important role in morphogenesis and testis devel opment), ATRX (a transcriptional regulator expressed dur ing development), and ARX (a homeobox-containing gene expressed during development), as well as chromosomal aberrations involving key genes such as a DMRT1 (hemizy gosity), DAX1 (duplication), and WNT4 (duplication) 115,346,347 (Table 8.3) .

II

TABLE 8.3 Genes Associated with 46,XY Partial Gonadal Dysgenesis

Müllerian Structures External Genitalia Associated Features

Gene Locus

Inheritance Gonad

Single-gene disorders WT1 11p13

+/ −

Autosomal

Dysgenetic testis

Female or ambiguous

Wilms tumor, renal anomalies, gonadal tumors

dominant

+/ −

SF1

Dysgenetic testis

Female or ambiguous

Adrenal failure (some)

9q33

Autosomal

dominant/ recessive

+/ −

SRY

Yp11.3

Y

Dysgenetic testis/ ovotestis Dysgenetic testis/ ovotestis

Female or ambiguous

+/ −

SOX9

17q24-5 Autosomal dominant

Female or ambiguous

Campomelic dysplasia

DHH

12q13.1

Autosomal recessive

Dysgenetic testis

+

Female

−

ATRX

Xq13.3

X

Dysgenetic testis

Female, ambiguous, or male

Alpha thalassemia, mental retardation Lissencephaly, epilepsy, temperature instability

−

ARX

Xp22.13 X

Dysgenetic testis

Ambiguous

Chromosomal aberrations DMRT1 9p24.3

+/ − +/ −

Hemizygosity Dysgenetic testis

Female or ambiguous

Mental retardation

DAX1

Xp21.3

Duplication Xp21 Duplication 1p35

Dysgenetic

Female or ambiguous

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WNT4

1p35

Dysgenetic testis

+

Ambiguous

Mental retardation

Data from Lee PA, Houk CP, Ahmed SF, Hughes IA, Consensus statement on management of intersex disorders. International Consensus Conference on Intersex, Pediatrics 118:e488, 2006.