Overview of Y-Linked Disorders
Y-linked disorders are genetic diseases caused by mutations or deletions of genes on the Y chromosome. The Y chromosome is the male sex chromosome; only males have the Y chromosome; females do not. Therefore, Y-linked disorders can only be inherited from father to son; females do not get sick or carry the disease-causing genes. There are very few types of Y-linked disorders because the Y chromosome has very few genes—about 200. The currently known Y-linked disorders include Y chromosome infertility, Swyer syndrome, and 46, the XY disorder of sex development.
Y Chromosome Infertility
Y chromosome infertility is a condition that affects the production of sperm and causes male infertility, which means it is difficult or impossible for affected men to father children. An affected man’s body may produce no mature sperm cells (azoospermia), fewer than the usual number of sperm cells (oligospermia), or sperm cells that are abnormally shaped or that do not move properly. Men with Y chromosome infertility usually have no obvious symptoms related to the condition, although physical examination may reveal small testes. Y chromosome infertility is usually caused by deletions of genetic material in regions of the Y chromosome called azoospermia factor (AZF) A, B, or C. Genes in these regions are believed to provide instructions for making proteins involved in sperm cell development, although the specific functions of these proteins are not well understood. Diagnostic methods for this condition may include chromosomal analysis, genetic testing, semen analysis, etc.
The main treatment option for Y chromosome infertility is to use assisted reproductive technologies (ART), such as in vitro fertilization using intracytoplasmic sperm injection (ICSI). ICSI is an in vitro fertilization procedure in which spermatozoa retrieved from ejaculate (in men with oligospermia) or extracted from testicular biopsies (in men with azoospermia) are injected into an egg harvested from the female partner. There is currently no effective gene therapy for Y chromosome infertility. However, some laboratory studies have explored the use of gene editing technologies such as CRISPR/Cas9 to repair Y chromosome deletions or add deletion genes that cause Y chromosome infertility. These technologies are expected to provide a fundamental cure for Y chromosome infertility in the future, but many technical and ethical hurdles still need to be overcome.
Swyer Syndrome
Swyer syndrome is a rare genetic disorder that affects sexual development. The patients have a 46, XY chromosome pattern but female external and partial internal genitalia and underdeveloped sex glands (ovaries or testes) that consist of fibrous tissue, called streak gonads. The condition is usually diagnosed during puberty when the patients do not have menstruation (primary amenorrhea). The causes of Swyer syndrome may involve mutations in several genes, such as SRY, DHH, NR5A1, CBX2, and DMRT1/2. The diagnosis of Swyer syndrome mainly relies on chromosome analysis, hormone level tests, and a gonadal tissue biopsy. The diagnosis of Swyer syndrome mainly relies on chromosome analysis, hormone level tests, and a gonadal tissue biopsy. Chromosome analysis can determine the patient's chromosome pattern; hormone level tests can assess the patient's gonadal function; and gonadal tissue biopsy can identify the patient's gonad type and cancer risk.
The treatment goals for Swyer syndrome are to promote feminization, prevent osteoporosis, reduce cancer risk, and provide fertility options. Gonadectomy is a common surgical treatment that can remove the streaked gonads that have a high risk of cancer and prepare for hormone replacement therapy. The timing of surgery varies depending on the individual, but it is generally recommended within a year of diagnosis or before puberty. Hormone replacement therapy is a medication treatment that can supplement the patient's lack of estrogen and progesterone, induce breast and uterine development, induce menstruation, and prevent osteoporosis. Hormone replacement therapy usually starts at puberty and lasts until menopause. The dose and mode of hormone replacement therapy vary depending on the individual and need regular monitoring and adjustment. Assisted reproductive technology is an assisted reproduction method that can help patients achieve pregnancy and childbirth. Since the patients do not have eggs, they need to use donated eggs or embryos for in vitro fertilization. If the patients have a uterus, they can undergo embryo transfer and deliver the baby by natural birth or cesarean section. If the patients do not have a uterus, they need to rely on a surrogate mother to complete the pregnancy and delivery process. Currently, there is no gene therapy for Swyer syndrome, but with the advancement of gene editing technology, there may be more possibilities in the future
46, XY disorder of sex development
46, XY disorder of sex development (DSD) is a condition that affects sex development and causes individuals with a male chromosomal pattern (one X chromosome and one Y chromosome) to have genitalia that is not clearly male or female. The possible causes of this condition include abnormal testicular development, defects in androgen synthesis or action, LH receptor deficiency, AMH synthesis or action deficiency, etc. The possible symptoms of this condition include hirsutism, clitoral hypertrophy, primary amenorrhea, breast hypoplasia, micropenis, cryptorchidism, etc. The possible diagnostic methods for this condition include chromosomal analysis, hormone level measurement, ultrasound examination, genetic testing, etc.
Currently, the treatment options for 46, XY DSD mainly include surgical treatment, hormone replacement therapy, and psychological support. Depending on the patient’s gender identity and reproductive function needs, corresponding genital reconstruction surgeries can be performed, such as clitoroplasty, vaginoplasty, phalloplasty, etc. In addition, since the patient’s gonads (non-functional testes or ovaries) have a risk of developing cancer, it is usually recommended to remove them as soon as possible after diagnosis. Since the patient lacks normal gonadal hormone secretion, estrogen or testosterone replacement therapy is needed to promote the development of secondary sexual characteristics, maintain bone health, prevent osteoporosis, and improve the patient's psychological state. Since 46, XY DSD can cause troubles for the patient in terms of identity recognition, social adaptation, sexual function, etc., professional psychological counseling and support are needed to help the patient build confidence and a positive attitude towards life. As for gene therapy options, there is currently no effective gene therapy method for 46, XY DSD. However, some laboratory studies have explored the use of gene editing techniques (such as CRISPR/Cas9) to repair gene mutations or deletions that cause 46, XY DSD. These techniques may provide a fundamental cure for 46, XY DSD in the future, but they still need to overcome many technical and ethical barriers.
References
- Fan Y, et al. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2023.
- Fallat ME, et al. Swyer Syndrome/46 XY Gonadal Dysgenesis: Remove the Tubes or Not? J Pediatr Adolesc Gynecol. 2021 Dec;34(6):771-772.
- Cherukuri S, et al. The Mysteries of Primary Amenorrhea: Swyer Syndrome. Cureus. 2022 Aug 19;14(8):e28170.
- Anwar A, et al. Swyer Syndrome: A Case of Dysgerminoma Solely within the Fallopian Tube. J Pediatr Adolesc Gynecol. 2021 Dec;34(6):869-871.
- Wisniewski AB, et al. Management of 46,XY Differences/Disorders of Sex Development (DSD) Throughout Life. Endocr Rev. 2019 Dec 1;40(6):1547-1572.
- Carvalho FM, et al. 46,XY disorder of sex development (DSD) due to 17β-hydroxysteroid dehydrogenase type 3 deficiency. J Steroid Biochem Mol Biol. 2017 Jan;165(Pt A):79-85.
