Gonadal dysgenesis

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Gonadal dysgenesis
Specialty Medical genetics Edit this on Wikidata

Gonadal dysgenesis is classified as any congenital developmental disorder of the reproductive system [1] in the male or female. It is the defective development of the gonads in an embryo, [2] with reproductive tissue replaced with functionless, fibrous tissue, termed streak gonads. [3] 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. [4]

Gonadal development is a genetically controlled process by the chromosomal sex (XX or XY) which directs the formation of the gonad (ovary or testis). [4]

Differentiation of the gonads requires a tightly regulated cascade of genetic, molecular and morphogenic events. [5] At the formation of the developed gonad, steroid production influences local and distant receptors for continued morphological and biochemical changes. [5] This results in the appropriate phenotype corresponding to the karyotype (46,XX for females and 46,XY for males). [5]

Gonadal dysgenesis arises from the failure of signalling in this tightly regulated process during early foetal development. [6] [7]

Manifestations of gonadal dysgenesis are dependent on the aetiology and severity of the underlying defect. [7]

Causes[edit]

Pathogenesis[edit]

46,XX Gonadal Dysgenesis[edit]

46,XX gonadal dysgenesis is characteristic of female hypogonadism with a karyotype of 46,XX. [8] Streak ovaries are present with non-functional tissues unable to produce the required sex steroid oestrogen [9] Low levels of oestrogen effect the HPG axis with no feedback to the anterior pituitary to inhibit the secretion of FSH and LH. [9] FSH and LH are secreted at abnormal elevated levels. [9] Improper levels of these hormones will cause a failure to initiate puberty, undergo menarche, and develop secondary sex characteristics. [9] [10] If sufficient functional ovarian tissue is present, limited menstrual cycles can occur. [9]

The pathogenesis of 46,XX gonadal dysgenesis is unclear, as it can manifest from a variety of dysregulations. [6] Interruption during ovarian development in embryogenesis can cause 46,XX gonadal dysgenesis with cases of abnormalities in the FSH receptor [10] [11] and mutations in steroidogenic acute regulatory protein (StAR protein) which regulates steroid hormone production. [10]

46,XY Gonadal Dysgenesis[edit]

46,XY gonadal dysgenesis is characteristic of male hypogonadism with karyotype 46,XY. [12]

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). [12] The male gonad is dependent on SRY and the signalling pathways initiated to several other genes to facilitate testis development. [9]

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. [9] [13] If a single or combination of these genes are mutated or deleted, downstream signalling is disrupted, leading to malformation of male external genitalia. [14]

SRY acts on gene SOX9 which drives Sertoli cell formation and testis differentiation. [15] 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.[4] 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.[4] The lack of the male associated steroid hormones drives Müllerian duct development and perusal of the development of female genitalia. [12]

Gonadal streaks replace the tissues of the testes, resembling ovarian stroma absent of follicles. [14] 46,XY gonadal dysgenesis can remain unsuspected until delayed pubertal development is observed. [14]

Approximately 15% of cases of 46,XY gonadal dysgenesis carry de novo mutations in the SRY gene, [16] with an unknown causation for the remaining portion of 46,XY gonadal dysgenesis patients. [15]

Mixed Gonadal Dysgenesis[edit]

Mixed gonadal dysgenesis, also known as X0/XY mosaicism or partial gonadal dysgenesis [15] is a sex development disorder associated with sex chromosome aneuploidy and mosaicism of the Y chromosome. [14] Mixed gonadal dysgenesis is the presence of two or more germ line cells. [17]

The degree of development of the male reproductive tract is determined by the ratio of germ line cells expressing the XY genotype. [15] [17]

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. [16] [17] The dysgenic testis can have adequate functional tissue to produce satisfactory levels of testosterone to cause masculinisation. [16] [17]

Mixed gonadal dysgenesis is poorly understood at the molecular level. [17] The loss of the Y chromosome can occur from deletions, translocations, or migration failure of paired chromosomes during cell division. [16] [17] The chromosomal loss results in partial expression of the SRY gene, giving rise to abnormal development of the reproductive tract and altered hormones levels. [16] [17]

Turner syndrome[edit]

Turner syndrome, also known as 45,X or 45,X0, is a chromosomal abnormality characterised by a partial or completely missing second X chromosome [4] [18] [19] giving a chromosomal count of 45, instead of the correct count of 46 chromosomes. [18]

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. [4] [7]

The aetiology of Turner syndrome phenotype can be the result of haploinsufficiency, where a portion of critical genes are rendered inactive during embryogenesis. [4] [18] Normal ovarian development requires these vital regions of the X chromosome that are inactivated. [4] [20] Clinical manifestation include primary amenorrhea, hypergonadotropic hypogonadism, streak gonads, infertility and failure to develop secondary sex characteristics. [19] Turner Syndrome is not diagnosed until a delayed onset of puberty with Müllerian structures found to be in infantile stage. [4] Physical phenotypic characteristics include short stature, dysmorphic features and lymphedema at birth. [17] Comorbidities include heart defects, vision and hearing problems, diabetes and low thyroid hormone production. [4] [19]

Endocrine Disruptions[edit]

Endocrine disruptors interfere with the endocrine system and hormones. [21] Hormones are critical for the correct events in embryogenesis to occur. [20] Foetal development relies on the proper timing of the delivery of hormones for cellular differentiation and maturation. [4] Disruptions can cause sexual development disorders leading to gonadal dysgenesis. [22]

Diagnosis[edit]

Management[edit]

See also[edit]

References[edit]

  1. ^ Carreau S, Lejeune H (2001). "Andrology: Male Reproductive Health and Dysfunction". Andrologie. 11 (2): 95–97. doi:10.1007/BF03034401. 
  2. ^ Hughes I (2008). "Chapter 16 – The Testes: Disorders of Sexual Differentiation and Puberty in the Male' in Paediatric Endocrinology". Elsevier Health Sciences: 662–685. doi:10.1016/B978-1-4160-4090-3.X5001-7. 
  3. ^ "Gonadal Streak. Farlex Partner Medical Dictionary". 
  4. ^ a b c d e f g h i j k Balsamo A, Buonocore G, Bracci R, Weindling M (2012). "'Disorders of Sexual Development' in Neonatology". Springer. 
  5. ^ a b c Pieretti RV, Donahoe PK (2018). "'Pathogenesis and Treatment of Disorders of Sexual Development' in: Endocrine Surgery in Children". Springer. doi:10.1007/978-3-662-54256-9_18. 
  6. ^ a b Boizet-Bonhoure B (2015). "Development and Pathology of the Gonad". Seminars in Cell & Developmental Biology. 45: 57–58. doi:10.1016/j.semcdb.2015.11.009. PMID 26653403. 
  7. ^ a b c Jorgensen A, Johansen M, Juul A, Skakkebaek N, Main K, Rajpert-De Meyts E (2015). "Pathogenesis of germ cell neoplasia in testicular dysgenesis and disorders of sex development". Seminars in Cell & Developmental Biology. 45: 124–137. doi:10.1016/j.semcdb.2015.09.013. PMID 26410164. 
  8. ^ Quayle S, Copeland K (1991). "46, XX Gonadal Dysgenesis With Epibulbar Dermoid". American Journal of Medical Genetics: 4075–4076. doi:10.1002/ajmg.1320400114. PMID 1909490. 
  9. ^ a b c d e f g Nieschlag E, Behre H, Wieacker P, Meschede D, Kamischke A, Kliesch S (2010). "'Disorders at the Testicular Level' in Andrology". Springer. doi:10.1007/978-3-540-78355-8_13. ISBN 978-3-540-78355-8. 
  10. ^ a b c Grimbly C, Caluseriu O, Metcalfe P, Jetha M, Rosolowsky E (2016). "46, XY disorder of sex development due to 17-beta hydroxysteroid dehydrogenase type 3 deficiency: a plea for timely genetic testing". International Journal of Pediatric Endocrinology. 12: 1–5. doi:10.1186/s13633-016-0030-x. PMC 4908721Freely accessible. PMID 27307783. 
  11. ^ Aittomaki K, Lucena J, Pakarinen P, Sistonen P, Tapanainen J, Gromoll J, Kaskikari R, Sankila E (1995). "Mutations in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure". Cell. 82 (6): 959–968. doi:10.1016/0092-8674(95)90275-9. PMID 7553856. 
  12. ^ a b c Chen H, Huang H, Chang T, Lai C, Soong Y (2006). "Pure XY gonadal dysgenesis and agenesis in monozygotic twins". Fertility and Sterility. 85 (4): 1059.9–1059.11. doi:10.1016/j.fertnstert.2005.09.054. PMID 16580399. 
  13. ^ Barseghyan H, Symon A, Zadikyan M, Almalvez M, Segura E, Eskin A, Bramble M, Arboleda V, Bazter R, Neslon S, Delot E, Harley V, Vilain E (2018). "Identification of novel candidate genes for 46, XY disorders of sex development (DSD) using a C57BL/6J-Y POS mouse model". Biology of Sex Differences. 9 (8). doi:10.1186/s13293-018-0167-9. PMC 5789682Freely accessible. PMID 29378665. 
  14. ^ a b c d Han Y, Wang Y, Li Q, Dai S, He A, Wang E (2011). "Dysgerminoma in a case of 46, XY pure gonadal dysgenesis (Swyer Syndrome): a case report". Diagnostic Pathology. 6 (84): 1–5. doi:10.1186/1746-1596-6-84. PMC 3182960Freely accessible. PMID 21929773. 
  15. ^ a b c d Biason-Lauber A (2006). "The Battle of the Sexes: Human Sex Development and Its Disorders in Molecular Mechanisms of Cell Differentiation in Gonad Development". Results and Problems in Cell Differentiation. 58: 337–382. doi:10.1007/978-3-319-31973-5_13. PMID 27300185. 
  16. ^ a b c d e Bashamboo A, McElreavey K (2015). "Human sex-determination and disorders of sex-development (DSD)". Seminars in Cell & Developmental Biology. 45: 77–83. doi:10.1016/j.semcdb.2015.10.030. PMID 26526145. 
  17. ^ a b c d e f g h Donahoe P, Crawford J, Hendren W (1979). "Mixed Gonadal Dysgenesis, Pathogenesis and Management". Journal of Pediatric Surgery. 14 (3): 287–300. PMID 480090. 
  18. ^ a b c "Turner Syndrome: Condition Information". Eunice Kennedy Shriver National Institute of Health and Human Development. 2012. 
  19. ^ a b c Saenger P, Bondy A (2014). "'Chapter 16 - Turner Syndrome'". in Pediatric Endocrinology, (4th eds): 664–696. ISBN 9780323315258. 
  20. ^ a b Elsheikh M, Dunger D, Conway G, Wass J (2002). "Turners Syndrome in adulthood". Endocrine Reviews. 23 (1): 120–140. doi:10.1210/edrv.23.1.0457. 
  21. ^ "Endocrine Disruptors, National Institute of Environmental Health Sciences, 2013". 
  22. ^ Robert S (2010). "Pesticide atrazine can turn male frogs into females". Berkeley News, University of California. 

External links[edit]

Classification