Swyer syndrome
Encyclopedia
Swyer syndrome, or XY gonadal dysgenesis, is a type of hypogonadism
in a person whose karyotype
is 46,XY. The person is externally female with streak gonads, and left untreated, will not experience puberty
. Such gonads are typically surgically removed and a typical medical treatment would include hormone replacement therapy
with female hormones.
. The term “pure gonadal dysgenesis” (PGD) or Monica F's syndrome has been used to describe conditions 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 mixture 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. Patients with PGD have a normal karyotype but may have defects of a specific gene on a chromosome.
of a normal XY fetus is the development of testes. The early stages of testicular formation in the second month of gestation requires the action of several gene
s, of which one of the earliest and most important is SRY
, the sex-determining region of the Y chromosome. Mutations of SRY account for many cases of Swyer syndrome.
When such a gene is defective, the indifferent gonads fail to differentiate into testes in an XY (genetically male) fetus. Without testes, no testosterone
or antimüllerian hormone (AMH) is produced. Without testosterone
, the external genitalia fail to virilize
, resulting in normal female genitalia, and the wolffian duct
s fail to develop, so no internal male organs are formed. Without AMH, the Müllerian duct
s develop into normal internal female organs (uterus
, fallopian tube
s, cervix
, vagina
).
A baby who is externally a girl is born and is normal in all anatomic respects except that the child 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 until puberty fails to occur in people with Swyer syndrome. They appear to be normal girls and are generally considered so.
s and androgen
s), most of the secondary sex characteristic
s 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 gland
s can make limited amounts of androgens and are not affected by this syndrome, most of these persons will develop pubic hair, though it often remains sparse.
Evaluation of delayed puberty
usually reveals elevation of gonadotropin
s, 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 person 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.
and progesterone
therapy is typically commenced, prompting the development of female characteristics.
The consequences of streak gonads to a person with Swyer syndrome:
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.
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
.
Hypogonadism
Hypogonadism is a medical term for decreased functional activity of the gonads. Low testosterone is caused by a decline or deficiency in gonadal production of testosterone in males...
in a person whose karyotype
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
is 46,XY. The person is externally female with streak gonads, and left untreated, will not experience puberty
Puberty
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
. Such gonads are typically surgically removed and a typical medical treatment would include hormone replacement therapy
Hormone replacement therapy
Hormone replacement therapy may refer to:*Hormone replacement therapy *Hormone replacement therapy *Hormone replacement therapy *Androgen replacement therapy -See also:...
with female hormones.
Swyer syndrome as a form of "pure gonadal dysgenesis"
There are several forms of gonadal dysgenesisGonadal dysgenesis
Gonadal dysgenesis is a term used to describe multiple reproductive system development disorders. They are conditions of genetic origin. It is characterized by a progressive loss of primordial germ cells on the developing gonads of an embryo....
. The term “pure gonadal dysgenesis” (PGD) or Monica F's syndrome has been used to describe conditions 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
Turner syndrome
Turner syndrome or Ullrich-Turner syndrome encompasses several conditions in human females, of which monosomy X is most common. It is a chromosomal abnormality in which all or part of one of the sex chromosomes is absent...
(e.g., 45,X) and its variants, as well as those with mixed gonadal dysgenesis
Mixed gonadal dysgenesis
Mixed gonadal dysgenesis is a condition of unusual and asymmetrical gonadal development leading to an unassigned sex differentiation. A number of differences have been reported in the karyotype, most commonly a mosaicism 45,X/ 46, XY...
and a mixture 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
XX gonadal dysgenesis
This syndrome is inherited as an autosomal disease. It affects both males and females but the phenotype differs. In both sexes sensorineural deafness occurs but in females ovarian dysgenesis also occurs....
as PGD, 46,XX. Patients with PGD have a normal karyotype but may have defects of a specific gene on a chromosome.
Genetic associations
Types include:| Type | OMIM | Gene | Locus |
|---|---|---|---|
| 46,XY GONADAL DYSGENESIS, COMPLETE, SRY-RELATED | SRY SRY SRY is a sex-determining gene on the Y chromosome in the therians .This intronless gene encodes a transcription factor that is a member of the SOX gene family of DNA-binding proteins... |
Yp11.3 | |
| 46,XY GONADAL DYSGENESIS, COMPLETE OR PARTIAL, DHH-RELATED | DHH DHH (hedgehog) Desert hedgehog homolog , also known as DHH is a human gene. The protein encoded by this gene is involved in cell signaling. It is named for the Desert Hedgehog.-Function:... |
12q13.1 | |
| 46,XY GONADAL DYSGENESIS, COMPLETE OR PARTIAL, WITH OR WITHOUT ADRENAL FAILURE | NR5A1 | 9q33 | |
| 46,XY GONADAL DYSGENESIS, COMPLETE, CBX2-RELATED | CBX2 CBX2 (gene) Chromobox protein homolog 2 is a protein that in humans is encoded by the CBX2 gene. According to a New Scientist CBX2 controls human gender even more so than X/Y chromosomes.-Interactions:CBX2 has been shown to interact with RYBP.... |
17q25 | |
| 46,XY GONADAL DYSGENESIS, COMPLETE OR PARTIAL, WITH 9p24.3 DELETION | 9p24.3 |
Pathogenesis
The first known step of sexual differentiationSexual differentiation
Sexual differentiation is the process of development of the differences between males and females from an undifferentiated zygote...
of a normal XY fetus is the development of testes. The early stages of testicular formation in the second month of gestation requires the action of several gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s, of which one of the earliest and most important is SRY
SRY
SRY is a sex-determining gene on the Y chromosome in the therians .This intronless gene encodes a transcription factor that is a member of the SOX gene family of DNA-binding proteins...
, the sex-determining region of the Y chromosome. Mutations of SRY account for many cases of Swyer syndrome.
When such a gene is defective, the indifferent gonads fail to differentiate into testes in an XY (genetically male) fetus. Without testes, no testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
or antimüllerian hormone (AMH) is produced. Without testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
, the external genitalia fail to virilize
Virilization
In biology and medicine, virilization refers to the biological development of sex differences, changes that make a male body different from a female body. Most of the changes of virilization are produced by androgens...
, resulting in normal female genitalia, and the wolffian duct
Wolffian duct
The mesonephric duct is a paired organ found in mammals including humans during embryogenesis....
s fail to develop, so no internal male organs are formed. Without AMH, the Müllerian duct
Müllerian duct
Müllerian ducts are paired ducts of the embryo that run down the lateral sides of the urogenital ridge and terminate at the Müllerian eminence in the primitive urogenital sinus. In the female, they will develop to form the Fallopian tubes, uterus, cervix, and the upper two-third of the vagina; in...
s develop into normal internal female organs (uterus
Uterus
The uterus or womb is a major female hormone-responsive reproductive sex organ of most mammals including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species...
, fallopian tube
Fallopian tube
The Fallopian tubes, also known as oviducts, uterine tubes, and salpinges are two very fine tubes lined with ciliated epithelia, leading from the ovaries of female mammals into the uterus, via the utero-tubal junction...
s, cervix
Cervix
The cervix is the lower, narrow portion of the uterus where it joins with the top end of the vagina. It is cylindrical or conical in shape and protrudes through the upper anterior vaginal wall...
, vagina
Vagina
The vagina is a fibromuscular tubular tract leading from the uterus to the exterior of the body in female placental mammals and marsupials, or to the cloaca in female birds, monotremes, and some reptiles. Female insects and other invertebrates also have a vagina, which is the terminal part of the...
).
A baby who is externally a girl is born and is normal in all anatomic respects except that the child has nonfunctional streak gonads instead of ovaries
Ovary
The ovary is an ovum-producing reproductive organ, often found in pairs as part of the vertebrate female reproductive system. Ovaries in anatomically female individuals are analogous to testes in anatomically male individuals, in that they are both gonads and endocrine glands.-Human anatomy:Ovaries...
or testes. As girls' ovaries normally produce no important body changes before puberty
Puberty
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
, a defect of the reproductive system typically remains unsuspected until puberty fails to occur in people with Swyer syndrome. They appear to be normal girls and are generally considered so.
Diagnosis
Because of the inability of the streak gonads to produce sex hormones (both estrogenEstrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
s and androgen
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
s), most of the secondary sex characteristic
Secondary sex characteristic
Secondary sex characteristics are features that distinguish the two sexes of a species, but that are not directly part of the reproductive system. They are believed to be the product of sexual selection for traits which give an individual an advantage over its rivals in courtship and aggressive...
s do not develop. This is especially true of estrogenic changes such as breast development, widening of the pelvis and hips, and menstrual periods
Menstrual cycle
The menstrual cycle is the scientific term for the physiological changes that can occur in fertile women for the purpose of sexual reproduction. This article focuses on the human menstrual cycle....
. Because the adrenal gland
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
s can make limited amounts of androgens and are not affected by this syndrome, most of these persons will develop pubic hair, though it often remains sparse.
Evaluation of delayed puberty
Delayed puberty
Puberty is described as delayed puberty with exceptions when an organism has passed the usual age of onset of puberty with no physical or hormonal signs that it is beginning. Puberty may be delayed for several years and still occur normally, in which case it is considered constitutional delay, a...
usually reveals elevation of gonadotropin
Gonadotropin
Gonadotropins are protein hormones secreted by gonadotrope cells of the pituitary gland of vertebrates. This is a family of proteins, which include the mammalian hormones follitropin , lutropin , placental chorionic gonadotropins hCG and eCG and chorionic gonadotropin , as well as at least two...
s, 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
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
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 person with complete androgen insensitivity syndrome
Androgen insensitivity syndrome
Androgen insensitivity syndrome is a condition that results in the partial or complete inability of the cell to respond to androgens. The unresponsiveness of the cell to the presence of androgenic hormones can impair or prevent the masculinization of male genitalia in the developing fetus, as...
, 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
Upon diagnosis, estrogenEstrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
and progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
therapy is typically commenced, prompting the development of female characteristics.
The consequences of streak gonads to a person with Swyer syndrome:
- Gonads cannot make estrogen, so the breasts will not develop and the uterus will not grow and menstruate until estrogenEstrogenEstrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
is administered. This is often given transdermally. - Gonads cannot make progesterone, so menstrual periods will not be predictable until progestinProgestinA progestin is a synthetic progestogen that has progestinic effects similar to progesterone. The two most common uses of progestins are for hormonal contraception , and to prevent endometrial hyperplasia from unopposed estrogen in hormone replacement therapy...
is administered, still usually as a pill. - Gonads cannot produce eggsOvumAn ovum is a haploid female reproductive cell or gamete. Both animals and embryophytes have ova. The term ovule is used for the young ovum of an animal, as well as the plant structure that carries the female gametophyte and egg cell and develops into a seed after fertilization...
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 transferEmbryo transferEmbryo transfer refers to a step in the process of assisted reproduction in which embryos are placed into the uterus of a female with the intent to establish a pregnancy...
). - Streak gonads with Y chromosome-containing cells have a high likelihood of developing cancer, especially gonadoblastomaGonadoblastomaA gonadoblastoma is a complex neoplasm composed of a mixture of gonadal elements, such as large primordial germ cells, immature Sertoli cells or granulosa cells of the sex cord, and gonadal stromal cells.-Associations:...
. Streak gonads are usually removed within a year or so of diagnosis since the cancer can begin during infancy.
Gonadal dysgenesis and other similar or related conditions
Swyer syndrome represents one phenotypicPhenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
result of a failure of the gonads to develop properly, and hence is part of a class of conditions termed gonadal dysgenesis
Gonadal dysgenesis
Gonadal dysgenesis is a term used to describe multiple reproductive system development disorders. They are conditions of genetic origin. It is characterized by a progressive loss of primordial germ cells on the developing gonads of an embryo....
. There are many forms of gonadal dysgenesis.
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
Complete androgen insensitivity syndrome
Complete androgen insensitivity syndrome is a condition that results in the complete inability of the cell to respond to androgens. The unresponsiveness of the cell to the presence of androgenic hormones prevents the masculinization of male genitalia in the developing fetus, as well as the...
, partial X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
deletions, lipoid congenital adrenal hyperplasia
Lipoid congenital adrenal hyperplasia
Lipoid congenital adrenal hyperplasia is an endocrine disorder that is an uncommon and potentially lethal form of congenital adrenal hyperplasia...
, and Turner syndrome
Turner syndrome
Turner syndrome or Ullrich-Turner syndrome encompasses several conditions in human females, of which monosomy X is most common. It is a chromosomal abnormality in which all or part of one of the sex chromosomes is absent...
.