Y-Linked or Chromosomal
Principles
• Disorder of sex development
• Developmental regulatory gene
• Pseudoautosomal regions of the X and Y chromosomes
• Illegitimate recombination
• Incomplete penetrance
• Fertility loci
Major Phenotypic Features
• Age at onset: Prenatal
• Sterility
• Reduced secondary sexual features
• Unambiguous genitalia mismatched to chromosomal sex
History and Physical Findings
Ms. R., a 37-year-old executive, was pregnant with her first child. Because of her age-related risk for having a child with a chromosomal abnormality, she elected to have an amniocentesis to assess the fetal karyotype; the karyotype result was normal 46,XX. At 18 weeks' gestation, however, a fetal ultrasound scan revealed a normal male fetus; a subsequent detailed ultrasound scan confirmed a male fetus. Ms. R. had been in good health before and during the pregnancy with no infections or exposures to drugs during the pregnancy. Neither she nor her partner had a family history of a disorder of sexual development, sterility, or congenital anomalies. Reevaluation of the chromosome analysis confirmed a normal 46,XX karyotype, but fluorescence in situ hybridization identified a sex-determining region Y gene (SRY) signal on one X chromosome (Fig. C-41). At 38 weeks of gestation, Ms. R. had an uncomplicated spontaneous vaginal delivery of a phenotypically normal male child.
FIGURE C-41 Fluorescence in situ hybridization (FISH) analysis for the detection of the t(X;Y)(p22.3;p11.2) translocation in an SRY+ XX male. The chromosomes are counterstained with DAPI. The probe for SRY is a mixture of locus-specific sequences (red). X chromosomes are detected with sequences that map to the centromeric DNA (green). In normal cells, the red signal is observed only on the Y chromosome. In cells with the t(X;Y)(p22.3;p11.2) translocation, a red signal is observed on the abnormal chromosome X and a green signal on both X chromosomes. See Sources & Acknowledgments.
Background
Disease Etiology and Incidence
Disorders of sex development (DSDs) are panethnic and genetically heterogeneous. In patients with complete gonadal dysgenesis, point mutations, deletions, or translocations of SRY are among the most common causes of such disorders (see Chapter 6). Approximately 80% of 46,XX males with complete gonadal dysgenesis have a translocation of SRY onto an X chromosome, and 20% to 30% of 46,XY females with complete gonadal dysgenesis have a mutation or deletion of the SRY gene. The incidence of males with 46,XX testicular DSD and females with 46,XY complete gonadal dysgenesis is approximately 1 in 20,000 each.
Pathogenesis
SRY is a DNA-binding protein that alters chromatin structure by bending DNA. These DNA-binding and DNA-bending properties suggest that SRY regulates gene expression. During normal human development, SRY is necessary for the formation of male genitalia, and its absence is permissive for the formation of female genitalia. The precise mechanism through which SRY effects development of male genitalia is undefined, although some observations suggest that SRY, together with other related transcription factors encoded by autosomal or X-linked genes, is part of a critically balanced network of repressors and activators of the developmental pathways that lead to development of normal testes or ovaries (see Chapter 6).
SRY mutations identified in females with a 46,XY karyotype cause a loss of SRY function. Approximately 10% of XY females have a deletion of SRY (SRY− XY females [MIM 400044]), and an additional 10% have point mutations within SRY. The point mutations within SRY impair either DNA binding or DNA bending.
The SRY alteration observed in males with a 46,XX karyotype is a translocation of SRY from Yp to Xp (SRY+ XX males [MIM 400045]; Fig. C-41). During male meiosis, an obligatory crossing over occurs between the pseudoautosomal regions of Xp and Yp; this crossing over ensures proper segregation of the chromosomes and maintains sequence identity between the X and Y pseudoautosomal regions. On occasion, however, recombination occurs centromeric to the pseudoautosomal region and results in the transfer of Yp-specific sequences, including SRY, to Xp (see Chapter 6).
In addition to SRY, the Y chromosome contains at least three loci (azoospermic factor loci AZFa, AZFb, and AZFc) required for normal sperm development. The absence of these loci at least partially explains the infertility of males with 46,XX testicular DSD.
The X chromosome also contains several loci necessary for ovarian maintenance and female fertility. Oocyte development requires only a single X chromosome, but maintenance of those oocytes requires two X chromosomes. Consistent with these observations, female fetuses with 46,XY complete gonadal dysgenesis develop oocytes, but their ovarian follicles degenerate by birth or shortly thereafter. The absence of a second X chromosome therefore explains the infertility of such females (see Chapter 6).
Phenotype and Natural History
Males with 46,XX testicular DSD have many features of Klinefelter syndrome (47,XXY), including hypogonadism, azoospermia, hyalinization of seminiferous tubules, and gynecomastia. Despite decreased testosterone production, most patients enter puberty spontaneously, although they may require testosterone supplementation to attain full virilization. In contrast to patients with Klinefelter syndrome, most 46,XX male patients have normal to short stature, normal skeletal proportions, normal intelligence, and fewer psychosocial problems. Patients with an extensive portion of Yp on an X chromosome more closely resemble patients with Klinefelter syndrome.
Females with a 46,XY karyotype have complete gonadal dysgenesis and are usually taller than average women. These patients have physical features of Turner syndrome only when the deletion of SRY is associated with an extensive deletion of Yp. Because these patients have only streak gonads, they do not enter puberty spontaneously.
In contrast to the complete penetrance and relatively uniform expressivity observed with translocation or deletion of SRY, point mutations of SRY exhibit both incomplete penetrance and variable expressivity. Patients with SRY point mutations usually have complete gonadal dysgenesis, are taller than average women, and do not spontaneously develop secondary sexual characteristics. A few SRY point mutations, however, have been associated with both an infertile (complete gonadal dysgenesis) female phenotype and a fertile male phenotype within the same family.
Management
In patients with complete gonadal dysgenesis, the diagnosis of a DSD usually arises either because of discordance between the fetal ultrasound scan and fetal karyotype or because of absent or incomplete secondary sexual development and infertility. Confirmation that the DSD is secondary to an abnormality of SRY expression requires demonstration of the relevant SRY alteration.
For 46,XX testicular DSD patients, androgen supplementation is usually effective for virilization, but treatment of the azoospermia is not currently possible. Administration of supplemental androgens does not prevent gynecomastia. Patients need surgical treatment if the gynecomastia becomes sufficiently disconcerting or severe.
For 46,XY complete gonadal dysgenesis females, estrogen therapy is usually initiated at approximately 14 to 15 years of age to promote development of secondary sexual characteristics. Progesterone therapy is added to the regimen to induce menses either at the time of the first vaginal breakthrough bleeding or in the second year of estrogen therapy. In addition, because of the risk for development of gonadoblastoma, it is recommended that dysgenic gonads be removed once skeletal growth is complete.
As with all disorders of genital ambiguity or of discordance between genetic and phenotypic sex, the psychosocial management and counseling of the family and patient are extremely important. Many families and patients have difficulty understanding the medical data and making appropriate psychosocial adjustments.
Inheritance Risk
De novo illegitimate recombination is the most common cause of DSDs involving translocation or mutation of SRY; therefore most couples with an affected child have a low risk for recurrence in future children. Rarely, however, some cases arise as a result of inheriting an SRY deletion or translocation from a father with a balanced translocation between Xp and Yp. If the father is a translocation carrier, all children will be either an SRY+ XX boy or an SRY− XY girl. Because such patients are invariably sterile, they are at no risk for passing on the disorder.
Most 46,XY complete gonadal dysgenesis females with point mutations in SRY have de novo mutations. Parents of an affected child therefore usually have a low risk for recurrence in future children; however, because some SRY mutations have incomplete penetrance, normal fertile fathers can carry SRY mutations that may or may not cause DSDs among their XY children.
Questions for Small Group Discussion
1. Mutations of other genes, such as WT1, SOX9, NR5A1, and DAX1, can also result in a DSD. Compare and contrast the phenotypes observed with mutations in these genes with those observed with SRYmutations.
2. The association of SRY point mutations with an infertile female phenotype and a fertile male phenotype within the same family suggests either stochastic variation dependent on the reduced SRY activity or segregation of another locus that interacts with SRY. Why? How could this be resolved?
3. Mutations affecting steroid synthesis or steroid responsiveness are usually associated with ambiguous genitalia, whereas SRY mutations are generally associated with genitalia that, while mismatched with the chromosomal sex, are unambiguously male or female. Discuss the reasons for this generalization.
4. Discuss chromosomal, gonadal, and phenotypic sex, as well as psychological gender, and the importance of each to genetic counseling.
References
Ono M, Harley VR. Disorders of sex development: new genes, new concepts. Nat Rev Endocrinol. 2013;9:79–91.
Ostrer H. 46,XY disorder of sex development and 46,XY complete gonadal dysgenesis. [Available from] http://www.ncbi.nlm.nih.gov/books/NBK1547/.
Ostrer H. Disorders of sex development: an update. J Clin Endocrin Metab. 2014;99:1503–1509.
Vilain EJ. 46,XX testicular disorder of sex development. [Available from] http://www.ncbi.nlm.nih.gov/books/NBK1416/.