XY gonadal dysgenesis

Swyer syndrome
Classification and external resources
Specialty	medical genetics
ICD-10	Q56.4
ICD-9-CM	752.7
OMIM	400044
DiseasesDB	31464
MeSH	D006061

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 if left untreated, will not experience puberty. Such gonads are typically surgically removed (as they have a significant risk of developing tumors) and a typical medical treatment would include hormone replacement therapy.^[1] The syndrome was named by Gerald Swyer, an endocrinologist, based in London, United Kingdom.

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 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 (i.e., 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.^[2] 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	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	DMRT1/2	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 requires 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 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 wolffian ducts fail to develop, so no internal male organs are formed. Also, the lack of testosterone means that no dihydrotestosterone is formed and consequently the external genitalia fail to virilize, resulting in normal female genitalia. Without AMH, the Müllerian ducts develop into normal internal female organs (uterus, fallopian tubes, cervix, vagina).

A baby who is apparently a girl is born and is normal in most 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.

Diagnosis

Due to 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. As the adrenal glands 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 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 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.

Treatment

Upon diagnosis, estrogen and progesterone therapy is typically commenced, promoting 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 estrogen is administered. This is often given transdermally.
Gonads cannot make progesterone, so menstrual periods will not be predictable until progestin is administered, usually as a pill.
Gonads cannot produce eggs so conceiving children naturally is not possible. A woman with a uterus and ovaries but without female gamete is 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.^[3] 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 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.

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.

References

↑ Massanyi EZ1, Dicarlo HN, Migeon CJ, Gearhart JP (29 December 2012). "Review and management of 46,XY disorders of sex development.". J Pediatr Urol. 9 (3): 368–379. PMID 23276787. doi:10.1016/j.jpurol.2012.12.002.
↑ Specific Disorders of Ambiguous Genitalia
↑ Eh, Zheng; Liu, Weili (June 1994). "A familial 46 XY gonadal dysgenesis and high incidence of embryonic gonadal tumors". Chinese Journal of Cancer Research. 6 (2): 144–148. doi:10.1007/BF02997250. Originally published in Chinese as PMID 7307902

External links

Gonadal dysgenesis
Stoicanescu D, Belengeanu V, et al. (2006). "Complete Gonadal Dysgenesis With XY Chromosomal Constitution". Acta Endocrinologica (Buc). 2 (4): 465–70. doi:10.4183/aeb.2006.465.

Female congenital anomalies of the genitalia, including Intersex and DSD: (Q50–Q52; 752.0–752.4)

Internal

Uterine malformation	Müllerian agenesis Cervical agenesis Unicornuate uterus Uterus didelphys Bicornuate uterus Uterine septum Arcuate uterus
Vagina	Vaginal septum Vaginal hypoplasia

External

Extracellular ligand disorders
Cytokine	EDA Hypohidrotic ectodermal dysplasia Camurati–Engelmann disease
Ephrin	Craniofrontonasal dysplasia
WNT	Tetra-amelia syndrome
TGF	OFC 11
Fas ligand	Autoimmune lymphoproliferative syndrome 1B
Endothelin	EDN3 Waardenburg syndrome IVb Hirschsprung's disease 4
Other	DHH (DHH XY gonadal dysgenesis) BMP15 (Premature ovarian failure 4) TSHB (Congenital hypothyroidism 4) See also intercellular signaling peptides and proteins

Genetic disorder, protein biosynthesis: Transcription factor/coregulator deficiencies

(1) Basic domains

1.2	Feingold syndrome Saethre–Chotzen syndrome
1.3	Tietz syndrome

(2) Zinc finger
DNA-binding domains

2.1	(Intracellular receptor): Thyroid hormone resistance Androgen insensitivity syndrome PAIS MAIS CAIS Kennedy's disease PHA1AD pseudohypoaldosteronism Estrogen insensitivity syndrome X-linked adrenal hypoplasia congenita MODY 1 Familial partial lipodystrophy 3 SF1 XY gonadal dysgenesis
2.2	Barakat syndrome Tricho–rhino–phalangeal syndrome
2.3	Greig cephalopolysyndactyly syndrome/Pallister–Hall syndrome Denys–Drash syndrome Duane-radial ray syndrome MODY 7 MRX 89 Townes–Brocks syndrome Acrocallosal syndrome Myotonic dystrophy 2
2.5	Autoimmune polyendocrine syndrome type 1

(3) Helix-turn-helix domains

3.1	ARX Ohtahara syndrome Lissencephaly X2 MNX1 Currarino syndrome HOXD13 SPD1 Synpolydactyly PDX1 MODY 4 LMX1B Nail–patella syndrome MSX1 Tooth and nail syndrome OFC5 PITX2 Axenfeld syndrome 1 POU4F3 DFNA15 POU3F4 DFNX2 ZEB1 Posterior polymorphous corneal dystrophy Fuchs' dystrophy 3 ZEB2 Mowat–Wilson syndrome
3.2	PAX2 Papillorenal syndrome PAX3 Waardenburg syndrome 1&3 PAX4 MODY 9 PAX6 Gillespie syndrome Coloboma of optic nerve PAX8 Congenital hypothyroidism 2 PAX9 STHAG3
3.3	FOXC1 Axenfeld syndrome 3 Iridogoniodysgenesis, dominant type FOXC2 Lymphedema–distichiasis syndrome FOXE1 Bamforth–Lazarus syndrome FOXE3 Anterior segment mesenchymal dysgenesis FOXF1 ACD/MPV FOXI1 Enlarged vestibular aqueduct FOXL2 Premature ovarian failure 3 FOXP3 IPEX
3.5	IRF6 Van der Woude syndrome Popliteal pterygium syndrome

(4) β-Scaffold factors
with minor groove contacts

4.2	Hyperimmunoglobulin E syndrome
4.3	Holt–Oram syndrome Li–Fraumeni syndrome Ulnar–mammary syndrome
4.7	Campomelic dysplasia MODY 3 MODY 5 SF1 SRY XY gonadal dysgenesis Premature ovarian failure 7 SOX10 Waardenburg syndrome 4c Yemenite deaf-blind hypopigmentation syndrome
4.11	Cleidocranial dysostosis

(0) Other transcription factors

0.6	Kabuki syndrome

Ungrouped

Transcription coregulators

Coactivator:	CREBBP Rubinstein–Taybi syndrome
Corepressor:	HR (Atrichia with papular lesions)

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