XX gonadal dysgenesis is a type of female hypogonadism in which the ovaries do not function 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. Some cases are considered a severe version of premature ovarian failure where the ovaries fail before puberty.[1]
| XX gonadal dysgenesis | |
|---|---|
| Other names | XX ovarian dysgenesis, Perrault syndrome |
| Specialty | Medical genetics  |
Some forms of XX gonadal dysgenesis occurs with sensorineural deafness. This type is also known as Perrault syndrome, an autosomal recessive disease affecting both sexes. Males present only with the deafness.[2]
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.[3] Patients with PGD have a normal chromosomal constellation but may have localized genetic alterations.
Presentation
editRelated conditions
editXX gonadal dysgenesis is related to the Swyer syndrome in as much as both conditions have the same phenotype and clinical issues; however in Swyer syndrome the karyotype is 46,XY, and thus gonadectomy is recommended.[4]
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.[citation needed]
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).[5][6][7] It has been suggested to be a new type of syndrome.[5]
Pathogenesis
editThe cause of the condition is often unclear.
In cases without hearing involvement, some implicated genes are:[8]
- FOXL2, NOBOX, and FIGLA, related to ovarian development.[8] FOXL2 mutation can cause Blepharophimosis, ptosis, epicanthus inversus syndrome, which affects the eyes at the same time.[9]
- FSH receptor, related to signaling. Autosomal recessive.[10]
- BMP15, associated with X-linked form.[8]
- EIF2B2, EIF2B4, and EIF2B5, responsible for protein production (see eIF2).[8]
- PSMC3IP, autosomal recessive; mutation reduces estrogen-induced transcription of this gene.[8]
- Various genes involved in steroidogenesis[9]
In cases with hearing involvement (Perrault syndrome), the following genes are implicated:[11]
- LARS2[12] and HARS2,[13] two mitochondrial tRNA synthetase genes
- HSD17B4, involved in steroidogenesis and fatty acid metabolism
- TWNK, the mitochondrial helicase
- ERAL1, a mitochondrial rRNA chaperone[14]
- CLPP, a mitochondrial protease[15][16]
- RMND1, a protein involved in mitochondrial translation; causes kidney problems on top of classical Perrault symptons. Three cases are reported as of 2020.[17]
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.[citation needed]
Familial cases of XX gonadal dysgenesis are on record.[citation needed]
Diagnosis
editBecause 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.[citation needed]
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.[citation needed]
Treatment
editThe consequences to the girl with XX gonadal dysgenesis:[citation needed]
- 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.
- Her gonads cannot make progesterone, so her menstrual periods will not be predictable until she is given a progestin, still usually as a pill.
- 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
editIn 1951, Perrault reported the association of gonadal dysgenesis and deafness, now called Perrault syndrome.[18]
See also
editReferences
edit- ^ Ledig, S; Röpke, A; Wieacker, P (September 2010). "Copy number variants in premature ovarian failure and ovarian dysgenesis". Sexual Development. 4 (4–5): 225–32. doi:10.1159/000314958. PMID 20606390. S2CID 20694337.
- ^ Sampathkumar, G.; Veerasigamani, N. (2015). "Perrault syndrome — a rare case report". Journal of Clinical and Diagnostic Research. 9 (3): OD01-2. doi:10.7860/JCDR/2015/10992.5641. PMC 4413102. PMID 25954653.
- ^ Log In Problems
- ^ Sebastiano Campo (1998). "Laparoscopic gonadectomy in two patients with gonadal dysgenesis". The Journal of the American Association of Gynecologic Laparoscopists.
- ^ a b 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.
- ^ 46,XX Gonadal dysgenesis epibulbar dermoid at NIH's Office of Rare Diseases
- ^ ORPHANET – About rare diseases – About orphan drugs Archived January 13, 2005, at the Wayback Machine
- ^ a b c d e Witchel, Selma Feldman; Lee, Peter A. (2014). "Ambiguous genitalia". Pediatric Endocrinology. pp. 107–156.e1. doi:10.1016/B978-1-4557-4858-7.00014-7. ISBN 9781455748587.
- ^ a b Simpson, J.L. (2014). "Disorders of the Gonads, Genital Tract, and Genitalia". Reference Module in Biomedical Sciences: B9780128012383055604. doi:10.1016/B978-0-12-801238-3.05560-4. ISBN 9780128012383.
- ^ 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.
- ^ "OMIM Phenotypic Series — PS233400". www.omim.org. Retrieved 2020-11-18.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Oziębło, D.; Pazik, J.; Stępniak, I.; Skarżyński, H.; Ołdak, M. (2020). "Two Novel Pathogenic Variants Confirm RMND1 Causative Role in Perrault Syndrome with Renal Involvement". Genes. 11 (9): 1060. doi:10.3390/genes11091060. PMC 7564844. PMID 32911714.
- ^ 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.