Swyer's syndrome
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: XY gonadal dysgenesis
Overview
Swyer syndrome is a type of female hypogonadism in which no functional gonads are present to induce puberty in an otherwise normal girl whose karyotype is then found to be XY. Her gonads are found to be nonfunctional streaks. Estrogen and progesterone therapy is usually then commenced. The gonads are normally removed surgically because they do not function and may develop cancer.
Swyer syndrome as a form of "pure gonadal dysgenesis"
There are several forms of gonadal dysgenesis. The term “pure gonadal dysgenesis” (PGD) has been used to describe conditions of with normal sets of sex chromosomes (e.g., 46,XX or 46,XY), as opposed to those whose gonadal dysgenesis results from missing all or part of the second sex chromosome. The latter group includes those with Turner syndrome (e.g., 45,X) and its variants, as well as those with mixed gonadal dysgenesis and a mixtures of cell lines, some containing a Y chromosome (e.g., 46,XY/45,X).
Thus Swyer syndrome is referred to as PGD, 46,XY, and XX gonadal dysgenesis as PGD, 46,XX.[1] Patients with PGD have a normal chromosomal constellation but may have defects of a specific gene on a chromosome.
Classification
| Type | OMIM | Gene | Locus |
|---|---|---|---|
| 46,XY GONADAL DYSGENESIS, COMPLETE, SRY-RELATED | 400044 | SRY | Yp11.3 |
| 46,XY GONADAL DYSGENESIS, COMPLETE OR PARTIAL, DHH-RELATED | 233420 | DHH | 12q13.1 |
| 46,XY GONADAL DYSGENESIS, COMPLETE OR PARTIAL, WITH OR WITHOUT ADRENAL FAILURE | 612965 | NR5A1 | 9q33 |
| 46,XY GONADAL DYSGENESIS, COMPLETE, CBX2-RELATED | 613080 | CBX2 | 17q25 |
| 46,XY GONADAL DYSGENESIS, COMPLETE OR PARTIAL, WITH 9p24.3 DELETION | 154230 | 9p24.3 |
Pathogenesis
The first known step of sexual differentiation of a normal XY fetus is the development of testes. The early stages of testicular formation in the second month of gestation require the action of several genes, of which one of the earliest and most important is SRY, the "sex-determining region of the Y chromosome".
Mutations of SRY account for most cases of Swyer syndrome. When this gene is defective, testes fail to develop in an XY (genetically male) fetus. Without testes, no testosterone or antimullerian hormone are produced. Without testosterone the external genitalia fail to virilize, resulting in female genitalia. Without testosterone, the wolffian ducts fail to develop, so no internal male organs are formed. Without AMH the mullerian ducts develop into normal internal female organs (uterus, fallopian tubes, cervix, vagina).
A baby girl is born who is normal in all anatomic respects except that she has nonfunctional streak gonads instead of ovaries or testes. As girls' ovaries normally produce no important body changes before puberty, a defect of the reproductive system typically remains unsuspected in girls with Swyer syndrome until puberty fails to occur.
Diagnosis
Because of the inability of the streak gonads to produce sex hormones (both estrogens and androgens), most of the secondary sex characteristics do not develop. This is especially true of estrogenic changes such as breast development, widening of the pelvis and hips, and menstrual periods. Because the adrenal glands can make limited amounts of androgens and are not affected by this syndrome, most of these girls will develop pubic hair, though it often remains sparse.
Evaluation of delayed puberty usually reveals elevation of gonadotropins, indicating that the pituitary is providing the signal for puberty but the gonads are failing to respond. The next steps of the evaluation usually include checking a karyotype and imaging of the pelvis. The karyotype reveals XY chromosomes and the imaging demonstrates the presence of a uterus but no ovaries (the streak gonads are not usually seen by most imaging). Although an XY karyotype can also indicate a girl with complete androgen insensitivity syndrome, the absence of breasts, and the presence of a uterus and pubic hair exclude the possibility. At this point it is usually possible for a physician to make a diagnosis of Swyer syndrome.
Treatment
The consequences of streak gonads to a woman with Swyer syndrome:
- Gonads cannot make estrogen, so the breasts will not develop and the uterus will not grow and menstruate until estrogen is administered. This is often given through the skin now.
- Gonads cannot make progesterone, so menstrual periods will not be predictable until progestin is administered, still usually as a pill.
- Gonads cannot produce eggs so conceiving children naturally is not possible. A woman with a uterus but no ovaries may be able to become pregnant by implantation of another woman's fertilized egg (embryo transfer).
- Streak gonads with Y chromosome-containing cells have a high likelihood of developing cancer, especially gonadoblastoma. Streak gonads are usually removed within a year or so of diagnosis since the cancer can begin during infancy.
Swyer syndrome results from a failure of one of the earliest stages of differentiation of a genetic male: translation of the SRY gene to initiate testicular development. This syndrome represents one phenotypic result of a failure of the gonads to develop properly, and hence is part of a class of conditions termed gonadal dysgenesis. There are many forms of gonadal dysgenesis. As more and more specific genetic and molecular causes of gonadal dysgenesis become understood and defined, the eponymic terms such as Swyer syndrome are losing precision as diagnostic terms, though they still refer to a specific phenotype for purposes of medical recognition and management.
Swyer syndrome is an example of a condition in which an externally unambiguous female body carries dysgenetic, atypical, or abnormal gonads. Other examples include complete androgen insensitivity syndrome, partial X chromosome deletions, lipoid congenital adrenal hyperplasia, and Turner syndrome.
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Acknowledgements
The content on this page was first contributed by: C. Michael Gibson, M.S., M.D.