XX gonadal dysgenesis

XX gonadal dysgenesis is a type of female hypogonadism in which no functional ovaries are present to induce puberty in an otherwise normal girl whose karyotype is found to be 46,XX. With nonfunctional streak ovaries, she is low in estrogen levels (hypoestrogenic) and has high levels of FSH and LH. Estrogen and progesterone therapy is usually then commenced.

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Other namesGonadal dysgenesis, Perrault syndrome
SpecialtyMedical genetics 

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.

The term "pure gonadal dysgenesis" (PGD) has been used to distinguish a group of patients from gonadal dysgenesis related to Turner syndrome. In the latter a distinct chromosomal aberration is present, while in PGD the chromosomal constellation is either 46,XX or 46,XY. Thus XX gonadal dysgenesis is also referred to as PGD, 46 XX, and XY gonadal dysgenesis as PGD, 46,XY or Swyer syndrome.[1] Patients with PGD have a normal chromosomal constellation but may have localized genetic alterations.

Presentation

XX gonadal dysgenesis is related to the Swyer syndrome inasmuch as both conditions have the same phenotype and clinical issues; however in Swyer syndrome the karyotype is 46,XY, and thus gonadectomy is recommended.[2]

In Turner syndrome there is a demonstrable abnormality in or absence of one of the sex chromosomes that is the cause of the development of gonadal dysgenesis. In contrast XX gonadal dysgenesis has a normal female chromosome situation.

Another type of XX gonadal dysgenesis is known as 46,XX gonadal dysgenesis epibulbar dermoid, which follows the similar symptoms as the regular syndrome, though it also shows signs of epibulbar dermoid (eye disorder).[3][4][5] It has been suggested to be a new type of syndrome.[3]

Pathogenesis

The cause of the condition is often unclear. There are cases where abnormalities in the FSH-receptor have been reported.[6] Apparently either the germ cells do not form or interact with the gonadal ridge or undergo accelerated atresia so that at the end of childhood only a streak gonad is present, unable to induce pubertal changes. As girls' ovaries produce no important body changes before puberty, there is usually no suspicion of a defect of the reproductive system until puberty fails to occur.

Familial cases of XX gonadal dysgenesis are on record.

In one family mutations in the mitochondrial histidyl tRNA synthetase have been described as the cause.[7]

Diagnosis

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 girls will develop pubic hair, though it often remains sparse.

Evaluation of delayed puberty usually reveals the presence of pubic hair, but 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 XX chromosomes and the imaging demonstrates the presence of a uterus but no ovaries (the streak gonads are not usually seen by most imaging). At this point it is usually possible for a physician to make a diagnosis of XX gonadal dysgenesis.

Treatment

The consequences to the girl with XX gonadal dysgenesis:

  1. Her gonads cannot make estrogen, so her breasts will not develop and her uterus will not grow and menstruate until she is given estrogen. This is often given through the skin now.
  2. Her gonads cannot make progesterone, so her menstrual periods will not be predictable until she is given a progestin, still usually as a pill.
  3. Her gonads cannot produce eggs so she will not be able to conceive children naturally. A woman with a uterus but no ovaries may be able to become pregnant by implantation of another woman's fertilized egg (embryo transfer).

History

Perrault syndrome

In 1951, Perrault reported the association of gonadal dysgenesis and deafness, now called Perrault syndrome.[8] Currently, mutations in 6 different genes (LARS2,[9] HSD17B4, HARS2, TWNK, ERAL1[10] and CLPP[11][12]) are associated with the disease.[13]

See also

References
  1. Log In Problems
  2. Sebastiano Campo (1998). "Laparoscopic gonadectomy in two patients with gonadal dysgenesis". The Journal of the American Association of Gynecologic Laparoscopists.
  3. Quayle SA, Copeland KC (1991). "46,XX gonadal dysgenesis with epibulbar dermoid". Am. J. Med. Genet. 40 (1): 75–6. doi:10.1002/ajmg.1320400114. PMID 1909490.
  4. 46,XX Gonadal dysgenesis epibulbar dermoid at NIH's Office of Rare Diseases
  5. ORPHANET – About rare diseases – About orphan drugs Archived January 13, 2005, at the Wayback Machine
  6. Aittomäki, K; Lucena, JL; Pakarinen, P; Sistonen, P; Tapanainen, J; Gromoll, J; Kaskikari, R; Sankila, EM; et al. (1995). "Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure". Cell. 82 (6): 959–68. doi:10.1016/0092-8674(95)90275-9. PMID 7553856. S2CID 14748261.
  7. Pierce SB, Chisholm KM, Lynch ED, Lee MK, Walsh T, Opitz JM, Li W, Klevit RE, King MC (2011) Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. Proc Natl Acad Sci U S A.
  8. Perrault, M.; Klotz, B.; Housset, E. :Deux cas de syndrome de Turner avec surdi-mutite dans une meme fratrie. Bull. Mem. Soc. Med. Hop. Paris 16: 79-84, 1951.
  9. Pierce, Sarah B.; Gersak, Ksenija; Michaelson-Cohen, Rachel; Walsh, Tom; Lee, Ming K.; Malach, Daniel; Klevit, Rachel E.; King, Mary-Claire; Levy-Lahad, Ephrat (April 2013). "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. PMC 3617377. PMID 23541342.
  10. 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. (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.
  11. Jenkinson, Emma M.; Rehman, Atteeq U.; Walsh, Tom; Clayton-Smith, Jill; Lee, Kwanghyuk; Morell, Robert J.; Drummond, Meghan C.; Khan, Shaheen N.; Naeem, Muhammad Asif; Rauf, Bushra; Billington, Neil (April 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.
  12. Brodie, Erica J.; Zhan, Hanmiao; Saiyed, Tamanna; Truscott, Kaye N.; Dougan, David A. (December 2018). "Perrault syndrome type 3 caused by diverse molecular defects in CLPP". Scientific Reports. 8 (1): 12862. Bibcode:2018NatSR...812862B. doi:10.1038/s41598-018-30311-1. ISSN 2045-2322. PMC 6110781. PMID 30150665.
  13. "OMIM Phenotypic Series - PS233400". www.omim.org. Retrieved 2020-11-18.
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