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XX gonadal dysgenesis

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XX gonadal dysgenesis
Other namesXX ovarian dysgenesis, Perrault syndrome
SpecialtyMedical genetics Edit this on Wikidata

XX gonadal dysgenesis is a type of female hypogonadism in which the ovaries do not function to induce puberty in a person assigned female at birth, whose karyotype is 46,XX.[1] Individuals with XX gonadal dysgenesis have normal-appearing external genitalia as well as Müllerian structures (e.g., cervix, vagina, uterus). Due to the nearly absent or nonfunctional streak ovaries, the individual is low in estrogen levels (hypoestrogenic) and has high levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), hormones that cycle in the reproductive system.[2] As a result, the diagnosis often occurs after a concern for delayed puberty or amenorrhea. Treatment generally involves hormone replacement therapy with estrogen and progesterone.[3]

Presentation

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Signs and Symptoms

Individuals with XX gonadal dysgenesis appear phenotypical female with normal internal and external genitalia, bilateral streak gonads, and normal stature. Diagnosis commonly occurs in adolescence due to delayed puberty or amenorrhea. Some individuals may have some breast development, secondary amenorrhea, or ovarian follicles on imaging rather than the expected streak or hypoplastic ovaries.[4]

There have been some cases with other associated features such as sensorineural hearing loss (i.e., Perrault Syndrome), neurologic abnormalities, renal disease, malformation syndromes, clitoromegaly, or cerebellar ataxia.[5][6]

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The term "pure gonadal dysgenesis" (PGD) has been used to differentiate between gonadal dysgenesis related to Turner syndrome. Turner syndrome occurs due to partial or complete absence of one of the X chromosomes, resulting in 45,XO or 45,X. Associated characteristics include short stature, a broad shield-like chest, webbed neck, premature ovarian failure, and heart and kidney abnormalities to name a few.[7] People with XX gonadal dysgenesis do not generally have the characteristics listed before, other than the primary ovarian insufficiency.[8]

Meanwhile in PGD the chromosomal constellation is either 46,XX or 46,XY.Thus XX gonadal dysgenesis is also referred to as PGD, 46 XX. Meanwhile, XY gonadal dysgenesis is known as PGD, 46,XY or Swyer syndrome. Patients with PGD have a normal chromosomal constellation but may have localized genetic alterations. XX gonadal dysgenesis is related to Swyer syndrome in as much as both conditions have the same phenotype and clinical issues; however in Swyer syndrome the karyotype is 46,XY. Gonadectomy is recommended in these individuals due to the risk of malignant tumors due to mosaicism in the Y chromosome.[9]

Gonadal dysgenesis has also been related to other syndromes such as WAGR syndrome, Denys-Drash Syndrome, and Malouf syndrome.[10][11]

Pathogenesis

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XX gonadal dysgenesis is thought to be mainly caused by genetic defects in the pathways of ovarian development, specifically via autosomal-recessive inheritance since a positive family history or consanguinity has been noted. However, sporadic cases also have been reported. Ongoing research has identified some implicated genes, listed below, which often are in pathways of gonadal differentiation and formation as well as germ cell migration.[12][13][14]

In cases with hearing involvement (Perrault syndrome), the following genes are implicated:[22]

Diagnosis

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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 individuals will develop pubic hair, though it often remains sparse.[30]

Diagnosis usually occurs after evaluation for a concern of delayed puberty. Next steps involve laboratory studies, such as FSH and LH levels. Other laboratory studies such as testosterone, dehydroepiandrosterone, anti-Mullerian hormone, human chorionic gonadotropin, thyroid-stimulating hormone, and prolactin are apart of some algorithms to investigate primary amenorrhea.[31][32] Imaging can include a pelvic ultrasound or MRI, which would reveal normal internal genitalia such as a uterus but with streak gonads, which can be small and not easily visualized.[33][34] Genetic testing involves chromosomal analysis via karyotype to confirm XX chromosomes, rather than XO or XY as discussed in related syndromes above.[35][36]

Treatment

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Treatment involves hormone replacement therapy that mirrors physiologic levels that would be otherwise provided by functional ovaries. Induction of puberty and menstruation relies on estrogen, which can be given in oral or transdermal forms. Estrogen also has protective effects against osteopenia/osteoporosis as well as cardiovascular health and urogenital atrophy later in life.[37] Progesterone therapy is added after 12 months of estrogen or after menstruation has begun, whichever comes first, which decreases the risk of endometrial hyperplasia and subsequent cancer.[38] Combined oral contraceptives can also be used.[39]

In terms of fertility, pregnancy could be facilitated through egg donation and in vitro fertilization, as individuals with XX gonadal dysgenesis still have a functional uterus.[40]

Prognosis

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Prognosis is dependent on whether these individuals have any comorbidities or if the gonadal dysgenesis is apart of a syndrome. Without other somatic stigmata, complications include effects on fertility and other comorbidities generally associated with primary ovarian insufficiency such as bone health, cardiovascular risks, and psychosocial stressors.[41]

History

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In 1951, Perrault, Klotz, and Housset reported the association of gonadal dysgenesis and deafness in two sisters, and this presentation is now called Perrault syndrome.[42] The first described case of pure gonadal dysgenesis was in 1960, in a patient with presumed Turner syndrome but without the expected stigmata.[43]

See also

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References

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  1. ^ Stafford, Diane E. J. (2023-01-01), "Disorders of puberty", in Halpern-Felsher, Bonnie (ed.), Encyclopedia of Child and Adolescent Health (First Edition), Oxford: Academic Press, pp. 759–779, ISBN 978-0-12-818873-6, retrieved 2024-11-24
  2. ^ Thompson, Shelby; Wherrett, Diane (2025). "Disorders of Sex Development". Fanaroff and Martin's Neonatal-Perinatal Medicine (12th ed.). Philadelphia, PA: Elsevier. pp. 1750–1789. ISBN 978-0-323-93266-0.
  3. ^ Netter, Frank (2025). "Ovaries". Netter Collection of Medical Illustrations: Reprodctive System (3rd ed.). Philadelphia, PA: Elsevier. pp. 197–226. ISBN 978-0-323-88083-1.
  4. ^ Lobo, Roger (2022). "Primary and secondary amenorrhea and precocious puberty". Comprehensive Gynecology (8th ed.). Philadelphia, PA: Elsevier. pp. 781–800. ISBN 978-0-323-65399-2.
  5. ^ Thompson, Shelby; Wherrett, Diane (2025). "Disorders of Sex Development". Fanaroff and Martin's Neonatal-Perinatal Medicine (12th ed.). Philadelphia, PA: Elsevier. pp. 1750–1789. ISBN 978-0-323-93266-0.
  6. ^ Simpson, Joe Leigh; Rajkovic, Aleksandar (2004), "Germ Cell Failure and Ovarian Resistance: Human Genes and Disorders", The Ovary, Elsevier, pp. 541–557, doi:10.1016/b978-012444562-8/50033-1, ISBN 978-0-12-444562-8, retrieved 2024-12-01
  7. ^ Kikkeri, Shankar; Nagalli, Shivaraj (Aug 8, 2023). "Turner Syndrome". StatPearls. Florida: Treasure Island.
  8. ^ Smith, Roger (2024). "Gonadal Dysgenesis". Netter's Obstetrics and Gynecology (4th ed.). Philadelphia, PA: Elsevier. pp. 428–430. ISBN 978-0-44310739-9.
  9. ^ Netter, Frank (2025). "Ovaries". Netter Collection of Medical Illustrations: Reprodctive System (3rd ed.). Philadelphia, PA: Elsevier. pp. 197–226. ISBN 978-0-323-88083-1.
  10. ^ Stafford, Diane E. J. (2023-01-01), "Disorders of puberty", in Halpern-Felsher, Bonnie (ed.), Encyclopedia of Child and Adolescent Health (First Edition), Oxford: Academic Press, pp. 759–779, ISBN 978-0-12-818873-6, retrieved 2024-11-24
  11. ^ Thompson, Shelby; Wherrett, Diane (2025). "Disorders of Sex Development". Fanaroff and Martin's Neonatal-Perinatal Medicine (12th ed.). Philadelphia, PA: Elsevier. pp. 1750–1789. ISBN 978-0-323-93266-0.
  12. ^ Thompson, Shelby; Wherrett, Diane (2025). "Disorders of Sex Development". Fanaroff and Martin's Neonatal-Perinatal Medicine (12th ed.). Philadelphia, PA: Elsevier. pp. 1750–1789. ISBN 978-0-323-93266-0.
  13. ^ Laissue, Paul (2015-08-15). "Aetiological coding sequence variants in non-syndromic premature ovarian failure: From genetic linkage analysis to next generation sequencing". Molecular and Cellular Endocrinology. 411: 243–257. doi:10.1016/j.mce.2015.05.005. ISSN 0303-7207. PMID 25960166.
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  15. ^ Lussiana, Cristina; Guani, Benedetta; Mari, Caterina; Restagno, Gabriella; Massobrio, Marco; Revelli, Alberto (2008). "Mutations and Polymorphisms of the FSH Receptor (FSHR) Gene: Clinical Implications in Female Fecundity and Molecular Biology of FSHR Protein and Gene". Obstetrical & Gynecological Survey. 63 (12): 785. doi:10.1097/OGX.0b013e31818957eb. ISSN 0029-7828.
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  19. ^ Simpson, Joe Leigh (2008). "XX Gonadal Dysgenesis and Premature Ovarian Failure in 46,XX Individuals". The Global Library of Women's Medicine. doi:10.3843/GLOWM.10355. ISSN 1756-2228.
  20. ^ Er, Eren; Aşıkovalı, Semih; Özışık, Hatice; Sağsak, Elif; Gökşen, Damla; Onay, Hüseyin; Saygılı, Füsun; Darcan, Şükran; Özen, Samim (2024-01-08). "Investigation of the molecular genetic causes of non-syndromic primary ovarian ınsufficiency by next generation sequencing analysis". Archives of Endocrinology and Metabolism. 68. doi:10.20945/2359-4292-2022-0475. ISSN 2359-3997. PMC 10916837. PMID 37988663.
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  22. ^ "OMIM Phenotypic Series — PS233400". www.omim.org. Retrieved 2020-11-18.
  23. ^ Pierce, Sarah B.; Gersak, Ksenija; Michaelson-Cohen, Rachel; Walsh, Tom; Lee, Ming K.; Malach, Daniel; Klevit, Rachel E.; King, Mary-Claire; Levy-Lahad, Ephrat (2013-04-04). "Mutations in LARS2, Encoding Mitochondrial Leucyl-tRNA Synthetase, Lead to Premature Ovarian Failure and Hearing Loss in Perrault Syndrome". The American Journal of Human Genetics. 92 (4): 614–620. doi:10.1016/j.ajhg.2013.03.007. ISSN 0002-9297. PMC 3617377. PMID 23541342.
  24. ^ Pierce, Sarah B.; Chisholm, Karen M.; Lynch, Eric D.; Lee, Ming K.; Walsh, Tom; Opitz, John M.; Li, Weiqing; Klevit, Rachel E.; King, Mary-Claire (2011-04-19). "Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome". Proceedings of the National Academy of Sciences. 108 (16): 6543–6548. Bibcode:2011PNAS..108.6543P. doi:10.1073/pnas.1103471108. ISSN 0027-8424. PMC 3081023. PMID 21464306.
  25. ^ Pierce, Sarah B.; Walsh, Tom; Chisholm, Karen M.; Lee, Ming K.; Thornton, Anne M.; Fiumara, Agata; Opitz, John M.; Levy-Lahad, Ephrat; Klevit, Rachel E.; King, Mary-Claire (2010). "Mutations in the DBP-Deficiency Protein HSD17B4 Cause Ovarian Dysgenesis, Hearing Loss, and Ataxia of Perrault Syndrome". The American Journal of Human Genetics. 87 (2): 282–288. doi:10.1016/j.ajhg.2010.07.007. PMC 2917704. PMID 20673864.
  26. ^ Domínguez-Ruiz, María; García-Martínez, Alberto; Corral-Juan, Marc; Pérez-Álvarez, Ángel I.; Plasencia, Ana M.; Villamar, Manuela; Moreno-Pelayo, Miguel A.; Matilla-Dueñas, Antoni; Menéndez-González, Manuel; del Castillo, Ignacio (2019-08-28). "Perrault syndrome with neurological features in a compound heterozygote for two TWNK mutations: overlap of TWNK-related recessive disorders". Journal of Translational Medicine. 17 (1): 290. doi:10.1186/s12967-019-2041-x. ISSN 1479-5876. PMC 6712801. PMID 31455392.
  27. ^ Chatzispyrou, Iliana A.; Alders, Marielle; Guerrero-Castillo, Sergio; Zapata Perez, Ruben; Haagmans, Martin A.; Mouchiroud, Laurent; Koster, Janet; Ofman, Rob; Baas, Frank; Waterham, Hans R.; Spelbrink, Johannes N.; Auwerx, Johan; Mannens, Marcel M.; Houtkooper, Riekelt H.; Plomp, Astrid S. (2017-07-01). "A homozygous missense mutation in ERAL1, encoding a mitochondrial rRNA chaperone, causes Perrault syndrome". Human Molecular Genetics. 26 (13): 2541–2550. doi:10.1093/hmg/ddx152. ISSN 0964-6906. PMC 5965403. PMID 28449065.
  28. ^ Jenkinson, Emma; Rehman, Atteeq; Walsh, Tom; Clayton-Smith, Jill; Lee, Kwanghyul; Morell, Robert; Drummond, Meghan; Khan, Shaheen; Naeem, MuhammadAsif; Rauf, Bushra; Billington, Neil; Schultz, Julie; Urquhart, Jill; Lee, Ming; Berry, Andrew (2013). "Perrault Syndrome Is Caused by Recessive Mutations in CLPP, Encoding a Mitochondrial ATP-Dependent Chambered Protease". The American Journal of Human Genetics. 92 (4): 605–613. doi:10.1016/j.ajhg.2013.02.013. PMC 3617381. PMID 23541340.
  29. ^ Oziębło, Dominika; Pazik, Joanna; Stępniak, Iwona; Skarżyński, Henryk; Ołdak, Monika (2020-09-08). "Two Novel Pathogenic Variants Confirm RMND1 Causative Role in Perrault Syndrome with Renal Involvement". Genes. 11 (9): 1060. doi:10.3390/genes11091060. ISSN 2073-4425. PMC 7564844. PMID 32911714.
  30. ^ Breehl, Logen; Caban, Omar (2024), "Genetics, Gonadal Dysgenesis", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 30969708, retrieved 2024-12-01
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  35. ^ Breehl, Logen; Caban, Omar (2024), "Genetics, Gonadal Dysgenesis", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 30969708, retrieved 2024-12-01
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  37. ^ "Hormone Therapy in Primary Ovarian Insufficiency". www.acog.org. Retrieved 2024-12-01.
  38. ^ Witchel, Selma Feldman; Lee, Peter A. (2014), "Ambiguous genitalia", Pediatric Endocrinology, Elsevier, pp. 107–156.e1, doi:10.1016/b978-1-4557-4858-7.00014-7, ISBN 978-1-4557-4858-7, retrieved 2024-12-01
  39. ^ Smith, Roger (2024). "Gonadal Dysgenesis". Netter's Obstetrics and Gynecology (4th ed.). Philadelphia, PA: Elsevier. pp. 428–430. ISBN 978-0-44310739-9.
  40. ^ Williams, Cara (2023). "Paediatric Gynaecology and Differences in Sex Development". Clinical Obstetrics and Gynaecology (Fifth ed.). Scotland: Elsevier. pp. 33–47. ISBN 978-0-7020-8513-0.
  41. ^ "Primary Ovarian Insufficiency in Adolescents and Young Women". www.acog.org. Retrieved 2024-12-01.
  42. ^ "Bulletins et memoires de la societe de radiologie medicale de france". Tubercle. 19 (7): 331–332. 1938. doi:10.1016/s0041-3879(38)80015-5. ISSN 0041-3879.
  43. ^ Nistal, Manuel; Paniagua, Ricardo; González-Peramato, Pilar; Reyes-Múgica, Miguel (2015). "Perspectives in Pediatric Pathology Chapter 5 Gonadal Dysgenesis". Pediatric and Developmental Pathology. 18 (4): 259–278. doi:10.2350/14-04-1471-PB.1. ISSN 1093-5266. PMID 25105336.
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