XX gonadal dysgenesis

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XX gonadal dysgenesis
Other namesXX ovarian dysgenesis, Perrault syndrome
Specialty Medical genetics   OOjs UI icon edit-ltr-progressive.svg

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]

Contents

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

XX 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

The cause of the condition is often unclear.

In cases without hearing involvement, some implicated genes are: [8]

In cases with hearing involvement (Perrault syndrome), the following genes are implicated: [11]

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

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.[ 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

The consequences to the girl with XX gonadal dysgenesis:[ citation needed ]

  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

In 1951, Perrault reported the association of gonadal dysgenesis and deafness, now called Perrault syndrome. [18]

See also

Related Research Articles

<span class="mw-page-title-main">Turner syndrome</span> Disorder of the X chromosome

Turner syndrome (TS), also known as 45,X, or 45,X0, is a genetic disorder in which a person's cells have only one X chromosome or are partially missing an X chromosome leading to the complete or partial deletion of the pseudoautosomal regions in the affected X chromosome. Most people have two sex chromosomes. The chromosomal abnormality is often present in just some cells, in which case it is known as Turner syndrome with mosaicism. 45,X0 with mosaicism can occur in males or females, but Turner syndrome without mosaicism only occurs in females. Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low hairline at the back of the neck, short stature, and swollen hands and feet are seen at birth. Typically, those affected do not develop menstrual periods or breasts without hormone treatment and are unable to have children without reproductive technology. Heart defects, diabetes, and hypothyroidism occur in the disorder more frequently than average. Most people with Turner syndrome have normal intelligence; however, many have problems with spatial visualization that may be needed in order to learn mathematics. Vision and hearing problems also occur more often than average.

<span class="mw-page-title-main">Androgen insensitivity syndrome</span> Medical condition

Androgen insensitivity syndrome (AIS) is a condition involving the inability to respond to androgens, typically due to androgen receptor dysfunction.

<span class="mw-page-title-main">XY gonadal dysgenesis</span> Medical condition

XY complete gonadal dysgenesis, also known as Swyer syndrome, is a type of defect hypogonadism in a person whose karyotype is 46,XY. Though they typically have normal vulvas, the person has underdeveloped gonads, fibrous tissue termed "streak gonads", and if left untreated, will not experience puberty. The cause is a lack or inactivation of an SRY gene which is responsible for sexual differentiation. Pregnancy is often possible in Swyer syndrome with assisted reproductive technology. The phenotype is usually similar to Turner syndrome (45,X0) due to a lack of X inactivation. The typical medical treatment is hormone replacement therapy. The syndrome was named after Gerald Swyer, an endocrinologist based in London.

<span class="mw-page-title-main">Lipoid congenital adrenal hyperplasia</span> Medical condition

Lipoid congenital adrenal hyperplasia is an endocrine disorder that is an uncommon and potentially lethal form of congenital adrenal hyperplasia (CAH). It arises from defects in the earliest stages of steroid hormone synthesis: the transport of cholesterol into the mitochondria and the conversion of cholesterol to pregnenolone—the first step in the synthesis of all steroid hormones. Lipoid CAH causes mineralocorticoid deficiency in affected infants and children. Male infants are severely undervirilized causing their external genitalia to look feminine. The adrenals are large and filled with lipid globules derived from cholesterol.

<span class="mw-page-title-main">Sex-determining region Y protein</span> Protein that initiates male sex determination in therian mammals

Sex-determining region Y protein (SRY), or testis-determining factor (TDF), is a DNA-binding protein encoded by the SRY gene that is responsible for the initiation of male sex determination in therian mammals. SRY is an intronless sex-determining gene on the Y chromosome. Mutations in this gene lead to a range of disorders of sex development with varying effects on an individual's phenotype and genotype.

<span class="mw-page-title-main">XX male syndrome</span> Congenital condition where an individual with a 46,XX karyotype is male

XX male syndrome, also known as de la Chapelle syndrome, is a rare condition in which an individual with a 46,XX karyotype develops a male phenotype. Synonyms for XX male syndrome include 46,XX testicular difference of sex development

Ovotesticular syndrome is a rare congenital condition where an individual is born with both ovarian and testicular tissue. It is one of the rarest DSDs, with only 500 reported cases. Commonly, one or both gonads is an ovotestis containing both types of tissue. Although it is similar in some ways to mixed gonadal dysgenesis, the conditions can be distinguished histologically.

Gonadal dysgenesis is classified as any congenital developmental disorder of the reproductive system characterized by a progressive loss of primordial germ cells on the developing gonads of an embryo. One type of gonadal dysgenesis is the development of functionless, fibrous tissue, termed streak gonads, instead of reproductive tissue. 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.

<span class="mw-page-title-main">Sexual differentiation in humans</span> Process of development of sex differences in humans

Sexual differentiation in humans is the process of development of sex differences in humans. It is defined as the development of phenotypic structures consequent to the action of hormones produced following gonadal determination. Sexual differentiation includes development of different genitalia and the internal genital tracts and body hair plays a role in sex identification.

<span class="mw-page-title-main">Disorders of sex development</span> Medical conditions involving the development of the reproductive system

Disorders of sex development (DSDs), also known as differences in sex development or variations in sex characteristics (VSC), are congenital conditions affecting the reproductive system, in which development of chromosomal, gonadal, or anatomical sex is atypical.

<span class="mw-page-title-main">Steroidogenic factor 1</span> Protein-coding gene in humans

The steroidogenic factor 1 (SF-1) protein is a transcription factor involved in sex determination by controlling the activity of genes related to the reproductive glands or gonads and adrenal glands. This protein is encoded by the NR5A1 gene, a member of the nuclear receptor subfamily, located on the long arm of chromosome 9 at position 33.3. It was originally identified as a regulator of genes encoding cytochrome P450 steroid hydroxylases, however, further roles in endocrine function have since been discovered.

<span class="mw-page-title-main">Gonadoblastoma</span> Medical condition

A gonadoblastoma is a complex neoplasm composed of a mixture of gonadal elements, such as large primordial germ cells, immature Sertoli cells or granulosa cells of the sex cord, and gonadal stromal cells. Gonadoblastomas are by definition benign, but more than 50% have a co-existing dysgerminoma which is malignant, and an additional 10% have other more aggressive malignancies, and as such are often treated as malignant.

<span class="mw-page-title-main">Aromatase deficiency</span> Medical condition

Aromatase deficiency is a rare condition characterized by extremely low levels or complete absence of the enzyme aromatase activity in the body. It is an autosomal recessive disease resulting from various mutations of gene CYP19 (P450arom) which can lead to ambiguous genitalia and delayed puberty in females, continued linear growth into adulthood and osteoporosis in males and virilization in pregnant mothers. As of 2020, fewer than 15 cases have been identified in genetically male individuals and at least 30 cases in genetically female individuals.

<span class="mw-page-title-main">Complete androgen insensitivity syndrome</span> Medical condition

Complete androgen insensitivity syndrome (CAIS) is an AIS condition that results in the complete inability of the cell to respond to androgens. As such, the insensitivity to androgens is only clinically significant when it occurs in individuals who are exposed to significant amounts of testosterone at some point in their lives. The unresponsiveness of the cell to the presence of androgenic hormones prevents the masculinization of male genitalia in the developing fetus, as well as the development of male secondary sexual characteristics at puberty, but does allow, without significant impairment, female genital and sexual development in those with the condition.

46,XX/46,XY is a chimeric genetic condition characterized by the presence of some cells that express a 46,XX karyotype and some cells that express a 46,XY karyotype in a single human being. The cause of the condition lies in conception or utero with the aggregation of two distinct zygotes or blastocysts into a single embryo, which subsequently leads to the development of a single individual with two distinct cell lines, instead of a pair of fraternal twins. 46,XX/46,XY chimeras are the result of the merging of two non-identical twins. This is not to be confused with mosaicism or hybridism, neither of which are chimeric conditions, but is considered as an intersex condition.

Hypergonadotropic hypogonadism (HH), also known as primary or peripheral/gonadal hypogonadism or primary gonadal failure, is a condition which is characterized by hypogonadism which is due to an impaired response of the gonads to the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and in turn a lack of sex steroid production. As compensation and the lack of negative feedback, gonadotropin levels are elevated. Individuals with HH have an intact and functioning hypothalamus and pituitary glands so they are still able to produce FSH and LH. HH may present as either congenital or acquired, but the majority of cases are of the former nature. HH can be treated with hormone replacement therapy.

Follicle-stimulating hormone (FSH) insensitivity, or ovarian insensitivity to FSH in females, also referable to as ovarian follicle hypoplasia or granulosa cell hypoplasia in females, is a rare autosomal recessive genetic and endocrine syndrome affecting both females and males, with the former presenting with much greater severity of symptomatology. It is characterized by a resistance or complete insensitivity to the effects of follicle-stimulating hormone (FSH), a gonadotropin which is normally responsible for the stimulation of estrogen production by the ovaries in females and maintenance of fertility in both sexes. The condition manifests itself as hypergonadotropic hypogonadism, reduced or absent puberty, amenorrhea, and infertility in females, whereas males present merely with varying degrees of infertility and associated symptoms.

45,X/46,XY mosaicism, also known as X0/XY mosaicism and mixed gonadal dysgenesis, is a mutation of sex development in humans associated with sex chromosome aneuploidy and mosaicism of the Y chromosome. It is a fairly rare chromosomal disorder at birth, with an estimated incidence rate of about 1 in 15,000 live births. Mosaic loss of the Y chromosome in previously non-mosaic men grows increasingly common with age.

WNT4 deficiency is a rare genetic disorder that affects females and it results in the underdevelopment and sometimes absence of the uterus and vagina. WNT4 deficiency is caused by mutations of the WNT4 gene. Abnormally high androgen levels are found in the blood and can initiate and promote the development of male sex characteristics. This is seen as male pattern of hair growth on the chest and face. Those with this genetic defect develop breasts but do not have their period. Mayer–Rokitansky–Küster–Hauser syndrome is a related but distinct syndrome. Some women who have an initial diagnosis of MRKH have later been found to have WNT4 deficiency. Most women with MRKH syndrome do not have genetic mutations of the WNT4 gene. The failure to begin the menstrual cycle may be the initial clinical sign of WNT4 deficiency. WNT4 deficiency can cause significant psychological challenges and counseling is recommended.

Gonadal agenesis is a rare condition where an individual lacks both gonads.

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ Log In Problems
  4. ↑ Sebastiano Campo (1998). "Laparoscopic gonadectomy in two patients with gonadal dysgenesis". The Journal of the American Association of Gynecologic Laparoscopists.
  5. 1 2 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.
  6. ↑ 46,XX Gonadal dysgenesis epibulbar dermoid at NIH 's Office of Rare Diseases
  7. ↑ ORPHANET – About rare diseases – About orphan drugs Archived January 13, 2005, at the Wayback Machine
  8. 1 2 3 4 5 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.
  9. 1 2 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.
  10. ↑ 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.
  11. ↑ "OMIM Phenotypic Series — PS233400". www.omim.org. Retrieved 2020-11-18.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
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