Pure Gonadal Dysgenesis Individuals who are phenotypically female with sexual infantilism, primary amenorrhea, normal stature, and no karyotypic abnormalities (46,XX or 46,XY) have pure gonadal dysgenesis. The gonads are usually streaks, but there may be some development of secondary sexual characteristics, and a few episodes of uterine bleeding. Pure gonadal dysgenesis in a 46,XY individual (previously known as Swyer syndrome) can occur when mutations in the SRY (sex-determining region gene on the Y chromosome) located at Yp11 result in XY females without proper gonad development (11,12).
Mutations in many other genes such as SOX9, DAX1, WT-1, and SF1, which affect testicular differentiation and inhibit antim¨ullerian hormone production, result in XY pure gonadal dysgenesis (13). The SOX9 gene located at 17q24 has a role in testis differentiation and promotes antim¨ullerian hormone secretion. Some but not all mutations in the SOX9 gene cause XY sex reversal, along with camptomelic dysplasia (severe skeletal abnormalities) (14,15). Duplications of the DAX1 gene at Xp21 cause dose-sensitive XY sex reversal (16). DAX1 is hypothesized to antagonize the SRY gene, preventing testis development. Transgenic XY mice with overexpression of the DAX1 gene develop as phenotypic females, supporting this hypothesis (17). Mutation in the WT1 gene (Wilms’ tumor suppressor gene 1) located at 11p13 causes several different syndromes, depending on where the mutation in the gene occurs. In Frasier syndrome, there is alternative splicing, which causes the protein product to lack a highly conserved KTS triplet repeat. The normal +KTS isoform of the protein is believed to synergize with SF1 (steroidogenic factor 1) to promote the expression of antim¨ullerian hormone (AMH). Lack of the +KTS isoform in an XY patient results in normal female internal and external genitalia, streak gonads, and progressive glomerulopathy. These women frequently develop gonadoblastomas but rarely develop Wilms’ tumor, which is associated with mutations in other locations in the WT1 gene. XX patients with the mutation that prevents the +KTS isoform have similar kidney abnormalities but develop normal ovaries and genitalia (17–19). One XY patient with a heterozygous mutation of the SF1 gene had adrenal failure and sex reversal (20). SF1 is an orphan nuclear receptor that regulates AMH expression and regulates all the cytochrome P450 steroid hydroxylase enzymes (19). Duplication of 1p, which encodes the WNT4 gene, causes XY sex reversal. WNT4 may upregulate DAX1 transcripts. A TRX mutation causes XY sex reversal. Other genes that cause XY gonadal dysgenesis are likely to be identified. Mutations at 9p24 and 10q cause XY sex reversal, but the exact genes causing the defects are not elucidated (17,19,21).
XX pure gonadal dysgenesis can be caused by the presence of small Y chromosome fragments in the genome. It is estimated that 5% to 40% of patients with Ullrich-Turner syndrome have Y sequences by polymerase chain reaction (PCR), depending on the DNA sequences targeted for testing (22,23). If Y sequences are present, gonadectomy is advised because of the risk of gonadoblastoma (22).
In other patients with XX gonadal dysgenesis, the condition is likely to be caused by gene mutations that lead to ovarian insufficiency before pubertal development or after the development of secondary sexual characteristics, as discussed later in this chapter.