|Diagnostic method||pelvic examination (checking for maturation of external internal genitals), general examination (looking for secondary sexual characters), chromosome karyotyping, hormone levels like FSH, LH (which are increased in case of purely XX dysgenesis)|
Gonadal dysgenesis is classified as any congenital developmental disorder of the reproductive system in the male or female. It is the atypical development of the gonads in an embryo, with reproductive tissue replaced with functionless, fibrous tissue, termed streak gonads. Streak gonads are a form of aplasia, resulting in hormonal failure that manifests as sexual infantism and infertility, with no initiation of puberty and secondary sex characteristics.
Differentiation of the gonads requires a tightly regulated cascade of genetic, molecular and morphogenic events. At the formation of the developed gonad, steroid production influences local and distant receptors for continued morphological and biochemical changes. This results in the appropriate phenotype corresponding to the karyotype (46,XX for females and 46,XY for males).
- Pure gonadal dysgenesis 46,XX also known as XX gonadal dysgenesis
- Pure gonadal dysgenesis 46,XY also known as XY gonadal dysgenesis
- Mixed gonadal dysgenesis also known as partial gonadal dysgenesis, and 45,X/46,XY mosaicism
- Turner syndrome also known as 45,X or 45,X0
- Endocrine disruptions
46,XX Gonadal Dysgenesis
46,XX gonadal dysgenesis is characteristic of female hypogonadism with a karyotype of 46,XX.  Streak ovaries are present with non-functional tissues unable to produce the required sex steroid oestrogen  Low levels of oestrogen effect the HPG axis with no feedback to the anterior pituitary to inhibit the secretion of FSH and LH. FSH and LH are secreted at abnormal elevated levels. Improper levels of these hormones will cause a failure to initiate puberty, undergo menarche, and develop secondary sex characteristics. If sufficient functional ovarian tissue is present, limited menstrual cycles can occur.
The pathogenesis of 46,XX gonadal dysgenesis is unclear, as it can manifest from a variety of dysregulations. Interruption during ovarian development in embryogenesis can cause 46,XX gonadal dysgenesis with cases of abnormalities in the FSH receptor and mutations in steroidogenic acute regulatory protein (StAR protein) which regulates steroid hormone production.
46,XY Gonadal Dysgenesis
In embryogenesis, the development of the male gonads is controlled by the testis determining factor located on the sex-determining region of the Y chromosome (SRY). The male gonad is dependent on SRY and the signalling pathways initiated to several other genes to facilitate testis development.
The aetiology of 46,XY gonadal dysgenesis can be caused by mutations in the genes involved in testis development such as SRY, SOX9, WT1, SF1, and DHH. If a single or combination of these genes are mutated or deleted, downstream signalling is disrupted, leading to malformation of male external genitalia.
SRY acts on gene SOX9 which drives Sertoli cell formation and testis differentiation. An absence in SRY causes SOX9 to not be expressed at the appropriate time or concentration, leading to a deficiency in testosterone and Anti-Müllerian hormone production. Inadequate levels of testosterone and Anti-Müllerian hormone disrupts the development of Wolffian ducts and internal genitalia that are key to male reproductive tract development. The lack of the male associated steroid hormones drives Müllerian duct development and promotes the development of female genitalia.
Gonadal streaks replace the tissues of the testes, resembling ovarian stroma absent of follicles. 46,XY gonadal dysgenesis can remain unsuspected until delayed pubertal development is observed.
Mixed Gonadal Dysgenesis
Mixed gonadal dysgenesis, also known as X0/XY mosaicism or partial gonadal dysgenesis is a sex development disorder associated with sex chromosome aneuploidy and mosaicism of the Y chromosome. Mixed gonadal dysgenesis is the presence of two or more germ line cells.
Manifestations of mixed gonadal dysgenesis are highly variable with asymmetry in gonadal development of testis and streak gonad, accounted for by the percentage of cells expressing XY genotype. The dysgenic testis can have adequate functional tissue to produce satisfactory levels of testosterone to cause masculinisation.
Mixed gonadal dysgenesis is poorly understood at the molecular level. The loss of the Y chromosome can occur from deletions, translocations, or migration failure of paired chromosomes during cell division. The chromosomal loss results in partial expression of the SRY gene, giving rise to abnormal development of the reproductive tract and altered hormones levels.
Turner syndrome, also known as 45,X or 45,X0, is a chromosomal abnormality characterised by a partial or completely missing second X chromosome giving a chromosomal count of 45, instead of the correct count of 46 chromosomes.
Dysregulation in meiosis signalling to germ cells during embryogenesis may result in nondisjunction and monosomy X from separation failure of chromosomes in either the parental gamete or during early embryonic divisions.
The aetiology of Turner syndrome phenotype can be the result of haploinsufficiency, where a portion of critical genes are rendered inactive during embryogenesis. Normal ovarian development requires these vital regions of the X chromosome that are inactivated. Clinical manifestation include primary amenorrhea, hypergonadotropic hypogonadism, streak gonads, infertility and failure to develop secondary sex characteristics. Turner Syndrome is not diagnosed until a delayed onset of puberty with Müllerian structures found to be in infantile stage. Physical phenotypic characteristics include short stature, dysmorphic features and lymphedema at birth. Comorbidities include heart defects, vision and hearing problems, diabetes and low thyroid hormone production.
Endocrine disruptors interfere with the endocrine system and hormones. Hormones are critical for the correct events in embryogenesis to occur. Foetal development relies on the proper timing of the delivery of hormones for cellular differentiation and maturation. Disruptions can cause sexual development disorders leading to gonadal dysgenesis.
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Turner syndrome was first described independently by Otto Ulrich in 1930 and Henry Turner in 1938. 46,XX pure gonadal dysgenesis was first reported in 1960. 46,XY pure gonadal dysgenesis, also known as Swyer syndrome, was first described by Gim Swyer in 1955.
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