Genetics, Gonadal Dysgenesis


Article Author:
Logen Breehl


Article Editor:
Omar Caban


Editors In Chief:
Linda Lindsay


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
3/24/2019 12:47:32 PM

Introduction

Gonadal Dysgenesis is any of a multitude of conditions that can cause impaired development of the gonads: the testes or ovaries. The most notable of these conditions is Turner syndrome a quite common disorder affecting 1 in every 2500 live female births and possess a vast array of associated symptoms and complications.[1] Although there are a large number of syndromes that have gonadal dysgenesis as a component this article will focus on Turner syndrome as well as 46, XX, 46, XY, and mosaic forms of gonadal dysgenesis. Understanding the genetics behind gonadal dysgenesis will allow clinicians to better predict the disorder’s phenotypic presentation; in turn, improving both screening methods for associated medical problems and the ongoing care of those medical problems. This article will explore the cellular, biochemical, and molecular basis behind the genetic processes that cause gonadal dysgenesis and go on to study the clinical implications of this subset of disorders and the genetics behind this chromosomal condition.

Development

Gonadal dysgenesis is a genetic condition due to errors in cell division and or alterations in genetic material leading to complete or partial loss of gonadal development. The development of gonadal dysgenesis begins early on either at fertilization or shortly after in early stages of the embryo and fetus. Complete gonadal dysgenesis genotypes are known as either 46, XX or 46, XY. These patients with full gonadal dysgenesis exhibit streak gonads, female external genitalia and hypogonadotropic hypogonadism with associated amenorrhea and lack of secondary sexual characteristics but none of the other features of Turner syndrome described below.[2] The 46, XX type may develop due to genetic mutations or environmental factors affecting ovarian development leading to ineffective ovaries. 46, XX type gonadal dysgenesis is on the spectrum of conditions that cause premature ovarian failure. The XY type of complete gonadal dysgenesis also called Swyer syndrome, typically develops due to mutations of genes in the SRY sex determining region of the Y chromosome; multiple possible genes have been implicated here, but in many of the individual cases an exact cause is unknown.[2] Multiple genotypes have been discovered among Turner syndrome patients; the typical 45X type, as well as mosaic types such as 45X/46XX, 45X/46XX/47XXX, 45X/46XY considered partial gonadal dysgenesis. Additionally, some mosaics contain isochromosomes, ring chromosomes, and Xq deletions. Studies have found that as suspected mosaic forms of the disease tend to have decreased symptoms and phenotypic presentation due to some cell lines having normal genetic information.[3] 

The development of Turner syndrome stems from meiotic and mitotic errors that lead to a lack of a second X chromosome. Turner syndrome is known for a collection of symptoms including short stature, webbed neck, widely spaced nipples, amenorrhea and infertility, fetal hydrops, and cardiac problems such as a bicuspid aortic valve or coarctation of the aorta. Turner syndrome can cause a multitude of other conditions as well such as horseshoe kidney and sensorineural hearing loss. Most girls with Turner syndrome tend to have a normal intelligence level but may have issues with verbal and social skills.[4] The specific phenotypic presentations and manifestations of the different types of gonadal dysgenesis, as well as the mechanisms leading to each type, will be discussed below. 

Cellular

Two of the cellular processes involved in the development of gonadal dysgenesis include meiosis and mitosis. Mitosis is the process of cellular division in which DNA replication completes, and sister chromatids are separated to produce two identical cells. Meiosis, on the other hand, is a cellular division with two separate divisions. The first step of meiosis (meiosis I) after DNA replication homologous chromosomes are paired and may undergo crossover recombination with the exchange of DNA strands between the chromosomes. At the end of meiosis I homologous chromosomes separate and produce two new cells. Meiosis II results in these two cells completing another division in which sister chromatids separate producing four cells. These cells produced by meiosis contain half the genetic material of the parent cell that started the process.[5] The Turner syndrome type of gonadal dysgenesis can be the result of nondisjunction of sex chromosomes during either mitosis or meiosis. Nondisjunction results in unequal amounts of genetic material in the daughter cells produced. Non-disjunction typically occurs during meiosis I resulting in homologous chromosomes fail to separate. The effect of meiotic non-disjunction is gametes: ova or sperm that contain only 22 chromosomes instead of 23. Turner syndrome can be the result of an ovum lacking an X chromosome fertilized by a 23 X spermatozoon, or can be the result of a spermatozoon lacking an X or Y chromosome fertilizing a normal ovum resulting in the typical 45, X. Recent studies have found that 70 to 80% of Turner syndrome cases are the result of the loss of the paternal sex chromosome.[6] FISH studies have found increased amounts of X and Y chromosomes in ejaculated sperm indicating non-disjunction. However, Turner syndrome is relatively common, and if meiotic non-disjunction were the only cause we would expect to see the similar incidence of other disorders such as 47, XXY, 47, XYY, and 47, XXX, but we do not.

The exact mechanisms that make Turner syndrome so much more common than these other chromosomal disorders are unclear, but the belief is that non-disjunction and chromosomal loss during the first few rounds of mitosis in the embryo is the cause.[6] Non-disjunction during mitosis in the early stages of the fetus can also result in the formation of two separate lines of somatic cells 45X/46XX or 45X/46XY. The development of two cell lines of differing genetic makeup is called mosaicism and results in cells across the body having different genetic material which can also result in different phenotypic presentations in different parts of the body. Pure 46, XX gonadal dysgenesis is typically caused by alterations to genetic information needed for ovarian development which is present at the proximal Xp and distal Xq regions of the X chromosome. These alterations include gene translocations, deletions, and mutations. As discussed above during meiosis I homologous chromosomes can undergo crossing over and during this period translocations, and deletions can occur. The mutations causing 46, XX gonadal dysgenesis, can be sporadic or familial. Mutations in genes coding for the FSH receptor of the ovaries have implications in familial and sporadic cases.[7] Analysis of pedigrees of families with girls with 46, XX gonadal dysgenesis have found an autosomal recessive pattern although all the possible genes and mutations involved remain undiscovered.[8] A large number of 46, XX gonadal dysgenesis cases have links with the autosomal recessive condition congenital adrenal hyperplasia. Congenital adrenal hyperplasia is most often caused by a 21-hydroxylase enzyme deficiency, which leads to a buildup of the precursor for the enzyme 17-hydroxyprogesterone which is converted to testosterone causing virilization.[9] In addition to the genetic causes of 46 XX gonadal dysgenesis, the disorder can also stem from autoimmune disease, infection, and infarct. Complete 46, XY gonadal dysgenesis is due to deletion of the SRY gene in 10-15% of cases and due to a mutation in SRY or DDH genes in another 10-15% of cases.[7] True agonadism or a complete lack of gonads is yet another type of gonadal dysgenesis; however the exact mechanisms involved are unclear, but mutations in the WT1 gene have been seen in some cases.[7]

Biochemical

Turner Syndrome

  • The biochemical aspects of the genetics of Turner syndrome begin early on with X inactivation. X inactivation is the process in female somatic cells where one X chromosome is inactivated or shut off, and the genes of the active X chromosome under transcription and the ones of the inactive X chromosome are not. In this process, the XIST RNA produced from the X inactivation center coats one X chromosome by random selection and utilizes methylation and modification of histone proteins to repress euchromatin and inactivate the DNA of one X chromosome.[10] However, under normal circumstances 25% of the genes on the X chromosome escape silencing many of which have homologs on the Y chromosome in men. In Turner syndrome whether traditional 45, X or one of the many mosaic forms there is a decreased gene dosage since there is not a second X chromosome for genes to escape X inactivation from, and the lack of these genes on a secondary X chromosome is believed to be a large part of what causes the stigmata of Turner syndrome.[10] The SHOX gene is one of the many genes implicated in Turner syndrome and codes for two homeodomain isoforms. One of these isoforms is seen in bone marrow fibroblasts and implicated to be a part of the cause of short stature in Turner syndrome.[11] The SHOX gene encodes a transcription factor and has a 61 amino acid motif allowing for DNA binding. Alternative splicing creates two separate products from the transcription of the SHOX gene. SHOXa is a longer protein with 292 amino acids and is present in skeletal muscle, the heart, the pancreas, and fibroblasts of the bone marrow. SHOXb is a shorter protein of 225 amino acids and shows increased levels in bone marrow fibroblasts.[12] Another gene linked to Turner syndrome is the RPS4Y/X gene that is thought to be part of the cause of lymphedema seen in Turner syndrome patients. RPS4Y/X codes for a small subunit ribosomal protein.[11] ASMTL is a gene also linked to Turner syndrome and is thought to play a role in DNA methylation.[11] Lastly, the PPP2R3B gene is thought to be involved in cell cycle regulation problems involved in Turner syndrome.[11] These are some of the genes that have links to Turner syndrome and their associated biochemical mechanisms, several additional genes possibly linked to Turner syndrome will also be discussed in the following sections.

46, XX Pure Gonadal Dysgenesis 

  • The cases of 46 XX gonadal dysgenesis related to congenital adrenal hyperplasia most often are caused by mutations in the gene for 21-hydroxylase. This enzyme would typically catalyze the hydroxylation of 17-hydroxyprogesterone to 11 deoxycortisol. When this enzyme is deficient, it decreases the production of cortisol which increases ACTH which then increases cholesterol uptake by cells and increases production of pregnenolone. The increased steroid precursors shunt toward testosterone production leading to virilization.[9] Mutations in the gene for the FSH receptor of the ovary have also been implicated in certain cases of 46XX gonadal dysgenesis. Mutations in this G protein-coupled receptor leads to decreased or no signaling leading to decreased follicle formation in the ovary. Another gene BMP15 is involved in XX gonadal dysgenesis; this gene codes for a transforming factor beta involved in folliculogenesis. The products of this gene also stimulate granulosa cell proliferation. The transforming factor beta proteins first become translated into pre-proteins with a single peptide, as well as a pro and mature region. The individual parts of the preprotein are required for proper posttranslational processing to produce active proteins. The lack of these active proteins is believed to have connections to decreased follicle production as well as depletion of ovarian follicles altogether.[13]

46, XY Pure Gonadal Dysgenesis

  • Estimates are that about 15% of all cases of 46 XY gonadal dysgenesis are due to mutations in the SRY gene. Mutations are often found in the high mobility group part of the DNA binding region. The SRY gene is expressed in the early Sertoli cells forming in the testes and assists in the coordination of events leading to sexual differentiation. Sertoli cells promote the development of Leydig cells which go on to produce androgens and insulin-like factor3 leading to the regression of Mullerian duct structures and differentiation of Wolffian duct structures.[9] Mutations on SRY tend to lead to completely dysgenic gonad or a streak gonad whereas when SRY is normal, and other genes are the cause of dysgenesis some immature seminiferous tubules are observable.[7] Research has also found links to the genes SOX9, GATA4, FOG2, NR5A1, and WT1, many of which code for transcription factors.[9] Mutations in another gene MAP3K1 have been found in 13 to 18% of patients with 46, XY gonadal dysgenesis. The variants of MAP3K1 were found to cause a gain of function effects including phosphorylation of targets leading to decreased expression of SOX9. SOX9 is vital for testes development and is linked to β-catenin another factor in sexual development.[14]

NR5A1 Receptor

  • Mutations in this gene are the only monogenic mutation associated with spermatogenic and ovarian failure in 46 XY and 46 XX gonadal dysgenesis. NR5A1 has a two-zinc finger DNA binding domain and a 12-helix structure comparable to other nuclear receptors.[9] A recurrent point mutation has been documented in multiple individuals with ovarian failure and 46XX that stem from different families and different ethnicities. The mutation introduces a tryptophan residue preventing the protein from binding to the target DNA sequence. The current belief is that the NR5A1 receptor can interact with and activate beta-catenin. Beta-catenin is a regulator of sex development in multiple mammals and appears to need to be at certain levels for proper ovarian development, and when upregulated in an XY mammal can promote ovarian development while inhibiting proper testicular development.[9]

Molecular

Turner Syndrome

  • Turner Syndrome results in at least part of the cells of the body lacking a secondary X chromosome. However, normal female cells undergo X inactivation where there is the utilization of the genes of only one of the X chromosomes. The inactivated X chromosome is turned in to heterochromatin that is inactive. This process gets completed by genes in the X inactivation center near the long arm of the X chromosome Xq.[10] We would believe then that Turner syndrome would have no complications because after X inactivation a normal cell has the same amount of genetic material as a Turner syndrome cell, but this is not the case. The reason for this is that about 25% of the genes on the inactivated X chromosome avoid inactivation.[10] Loci on the X and Y chromosome have been mapped that reveal there are pseudoautosomal regions near the end of the Xp and Yp arms that maintain their nucleotide sequence throughout meiotic recombination and the genes in these areas escape X inactivation.[11] These areas are referred to as PAR1 and 2. Multiple genes have now been implicated as candidates to be involved in Turner SHOX/PHOG is one of the first genes in the Xp Yp pseudoautosomal region implicated and is believed to be involved in linear growth. Researchers found a German family with a point mutation in SHOX/PHOG to all have short stature further implicating this gene to be involved in the short stature of Turner syndrome.[11] Although there is evidence there implicating SHOX and short stature the extent of its contribution to short stature has not been established it appears as though SHOX may not be the only factor involved in short stature and itself may have an effect on other genes that lead to short stature. Another gene linked to Turner syndrome is RPS4X/RPS4Y although the data is a bit inconclusive about this gene it is thought to possibly be a factor in lymphedema and lymphatic abnormalities noted in Turner syndrome. This gene resides in the Yp region of the Y chromosome and has an X-linked homolog that escapes X inactivation.[11] Still another gene linked to Turner syndrome is ZFX/ZFY; it is not thought to be the sole cause of Turner syndrome but part of the gonadal dysgenesis symptoms. Mice studies have revealed that ZFX knockout mice had reduced germ cell numbers and heterozygous female mice showed a reduction in oocytes in comparison to their wild type counterparts but a reduction that was less than what was present in the knockout mice. This pattern of reduction in germ cell/oocyte number is similar to what appears in 45, X Turner syndrome patients versus their mosaic counterparts.[11] Additionally, recent studies utilizing embryonic stem cells with Turner syndrome have shown additional genes that might have involvement, including pseudoautosomal genes ASMTL and PPP2R3B which were found to have decreased expression in Turner syndrome cells, and CSF2RA which the Turner cells showed decreased upregulation. These genes are involved in processes affecting DNA methylation, the cell cycle, and placentation.[10] Lastly, there has been speculation that an X-linked gene DAX1 that suppresses testicular differentiation may cause the gonadal dysgenesis seen in 45X/45 XY mosaics.[15]

46, XX Pure Gonadal Dysgenesis

  • 46, XX complete gonadal dysgenesis is inherited in an autosomal recessive pattern, and several loci and genes have been implicated, however, the exact intricacies of what causes this type of gonadal dysgenesis is unclear. Inactivating mutations in the FSHR gene coding for the follicle stimulating hormone receptor is one of these genes linked to 46, XX dysgenesis mainly in the Finnish population. Mutation in this receptor leads to blocks in follicular development that cause the follicles to remain in the primary or antral stage. Depletion of the follicles is also an observation with this mutation.[13] Additionally, studies have tried to find other genes that might have specific links to 46, XX gonadal dysgenesis and the gene BMP15 appears to be a possible candidate. However, a definite link to gonadal dysgenesis remains unaffirmed. BMP15 is a gene that codes for proteins apart of the transforming growth factor-beta family made by oocytes. A rare amino acid substitution at p.A180T in BMP15 was present in a small number of patients with ovarian failure in several studies, additional studies have found that this amino acid substitution may be a rare polymorphism.[13] The cases linked to congenital adrenal hyperplasia due to 21-hydroxylase deficiency have direct links to over 100 different mutations in the CYP21A2 gene.[9] Regarding premature ovarian failure, a large number of genes including FMR1, AIRE, FOXL2, and POLG all share links to distinct syndromes that include ovarian failure among their symptoms. However, there have been no specific links made between these genes and 46XX gonadal dysgenesis.

46, XY Pure Gonadal Dysgenesis

  • The SRY gene on the Y chromosome essentially is a switch that turns on the processes of testicular development. The other main gene involved in male reproductive development is SOX9 which is involved in the action of Mullerian inhibiting substance. The Mullerian inhibiting substance is involved in inhibiting the development of female internal genitalia and allows for the male development to take place. Additionally, MAP3K1 is also a common gene linked to 46, XY gonadal dysgenesis and has been reported to be involved in 13 to 18% of patients. MAP3K1 expression downregulates SOX9 which then causes signaling to mirror what occurs in ovarian development leading to abnormal testicular development. The downregulation of the testicular development pathway leads to impaired gonadal development.[14]

Mechanism

The mechanisms of gonadal dysgenesis and specifically turner syndrome, 46 XX, 46 XY and mosaic forms of gonadal dysgenesis have been discussed in detail above. Although many genes have links with gonadal development and sexual differentiation, as well as a multitude of possible mutations, deletions, polymorphisms, and translocations associated with Turner syndrome, 46 XX, 46 XY and mosaic forms the exact mechanisms and genetic causes behind these disorders evades complete elucidation. DNA sequencing technologies have allowed investigations into specific genetic causes of these disorders. However, the particular pathway the genetic alterations go down to cause the phenotype we see are often unclear. The advancement of functional assays including in vivo, in vitro, and mouse models have allowed for better understanding of pathologic pathways to show the causal relationship between a change in a gene and the patient presentation.[9] At the moment these models we have in some respects are still limited. As genetic technologies continue to advance it appears that we will be able to gain an even better perspective into the causes of gonadal dysgenesis, as well as better insight into human sexual development.

Testing

Testing is not typically indicated for gonadal dysgenesis unless a diagnosis of gonadal dysgenesis or a syndrome that has gonadal dysgenesis as a symptom is suspected. Most patients with gonadal dysgenesis will begin a necessary workup for their symptoms including an FSH and LH level and possibly pelvic imaging. Prenatal diagnosis may be pursued in cases of abnormal maternal triple or quadruple screens, or if the fetus presents with atypical features in the womb. For example, Turner syndrome may present prenatally as coaction of the aorta, intrauterine growth restriction, oligohydramnios, polyhydramnios, increased nuchal translucency, cystic hygroma, or nonimmune hydrops.[1] Although these may be signs of Turner syndrome, a definitive diagnosis is only by a karyotype. A karyotype involves sending whole blood in a sodium heparin tube to the lab for testing, which may take up to a week, but a rushed result utilizing fluorescence in situ hybridization can identify monosomy X in under 24 hours.[4]

Early recognition can help prevent growth failure and hearing problems as well as better manage chronic renal and cardiac conditions associated with Turner syndrome. A karyotype in an older child is necessary when there is high suspicion of Turner syndrome. For example, if a child has growth delay or lack of signs of puberty and secondary sexual characteristics, or if a child exhibited other signs such as a webbed neck or widely spaced nipples, it would serve as an indication for a karyotype. If high suspicion exists of a Turner syndrome diagnosis and initial blood karyotype is normal, another tissue should be tested such as skin to determine the child’s genetic make-up. All patients should also have analysis to determine if there is any presence of a Y chromosome, due to the risk of gonadoblastoma and germ cell tumor. Analysis of a Y chromosome should be performed in the prenatal period as well.[1] Similar to Turner syndrome testing is also indicated for 46 XY complete gonadal dysgenesis when clinical findings suspect the diagnosis. A patient with delayed puberty or amenorrhea that has elevated basal LH and FSH levels and other causes for amenorrhea and delayed puberty ruled out can have a karyotype performed. Pelvic ultrasound or MRI may also reveal streak gonads which would indicate a karyotype.[16] 46 XX gonadal dysgenesis will present similarly to 46 XY gonadal dysgenesis with delayed puberty, amenorrhea, increased LH and FSH levels, and streak gonads may be present; again clinical suspicion is the leading indication for testing in this disorder.

In all patients with suspected gonadal dysgenesis as discussed with Turner syndrome determination of whether a Y chromosome is present, including mosaic as well as partial and fragment Y chromosomal forms is necessary due to risks of gonadoblastoma and germ cell tumor associated with the retained gonads. After initial analysis and karyotype a specialist, most likely an endocrinologist, might perform further testing for specific gene mutations to try to determine the cause of the patient’s gonadal dysgenesis as well as gain an understanding of what other symptoms they may develop based specific genetic alterations. The specific genetic testing to be performed is determined by the clinical presentation of the patient and their symptomatic presentation. The genes with known associations to their symptoms can be tested. In addition to the above testing patients who have evidence of a Y chromosome as well as evidence of a mass on the gonad will need to have a biopsy performed as well as tumor markers including AFP, LDH, and beta-hCG to determine the presence of gonadoblastoma or germ cell tumor.[16] Although genetic testing is an essential part of the diagnosis and management of gonadal dysgenesis the patients will undergo a multitude of testing during their lifetime to aid in the management of their condition. This testing can include basic labs CBC/CMP, echocardiography, renal ultrasound and much more to ensure all the patient's associated symptoms are addressed and managed.

Pathophysiology

Gonadal dysgenesis develops due to genetic alterations leading to impaired gonadal development. When the gonads do not develop properly, it leads to issues in the development of both internal and external genitalia. All patients with gonadal dysgenesis will have at least some dysfunction within the hypothalamic pituitary gonadal axis. The hypothalamus secretes GnRH which acts on the pituitary to release LH and FSH. LH and FSH go on to act on the gonads which in turn produce sex hormones in the form of estrogen and testosterone.[17] Due to a lack of gonadal development seen in gonadal dysgenesis, the gonads respond either minimally or not at all to LH and FSH stimulation, leading to decreased production of estrogen and testosterone as well as decreased production of ovarian follicles and sperm.

Complete 46 XY gonadal dysgenesis in which the lack of the SRY gene activating the body’s processes to enact male development results in the body relying on the default processes which allows the Mullerian structures to develop internally. Mullerian structures develop into the female anatomy including the fallopian tubes, uterus, and cervix. Due to the lack of testicular development in these males, there is a lack of testosterone production which inhibits the development of male external genitalia, so these males will tend to present with female external genitalia. Patients with incomplete or partial 46 XY gonadal dysgenesis, or patients with mosaic forms of the disease with a Y chromosome it appears that there is a mixture of development of both male and female internal genitalia. In the 46 XY with incomplete gonadal dysgenesis, it appears there is incomplete differentiation of the internal genitalia likely due to insufficient amounts of testosterone and Mullerian inhibiting hormone during the early stages of development. These patients range from having non-functional streak gonads to partially functioning gonads due to the incomplete development. Patient’s with mosaic forms of the disease as seen in Turner syndrome with cell lines containing a Y chromosome will also have a mixture of development resulting in partial or non-functioning gonads and internal genitalia. These patients will have ambiguous external genitalia due to the reduced influence of the Y chromosome.[7]

Patients with complete 46 XX gonadal dysgenesis will tend to have female internal and external genitalia and will typically have streaked or hypoplastic ovaries.[7] Turner syndrome patients have the same processes that affect their gonadal development resulting in atrophy of the ovarian follicles and the development of streak ovaries. As discussed above due to the gonads being unresponsive to FSH and LH female patients with gonadal dysgenesis will have amenorrhea, and most will be infertile. Some cases of spontaneous pregnancy in mosaic Turner syndrome patients have been documented, likely due to partial functioning of the ovary.[4] Males with gonadal dysgenesis will also tend to be infertile due to underdeveloped or lack of testes. The symptoms other than gonadal dysgenesis seen in syndromes such as Turner syndrome are due to the mutations and alterations in some of the secondary genes described above, for example the short stature seen in Turner syndrome which is believed to be caused by decreased sensitivity to growth hormone, decreased availability of growth hormone, or decreased production of growth hormone.[10]

Clinical Significance

Gonadal dysgenesis is clinically significant due to the issues it may cause to the physical and mental well-being of the patients affected by it. Patients with gonadal dysgenesis will likely need hormone therapy to develop appropriate secondary sexual characteristics. Even with hormone therapy a large percentage of these patients may not develop similarly to their peers and will remain infertile; this can have huge impacts on the patient’s mental health. Children and adults with gonadal dysgenesis may feel insecure about their physical appearance. For example, when an individual is genetically male but has female external genitalia as in 46, XY gonadal dysgenesis, it can be a point of concern and stress for both the patient and the patient’s parents. Females with gonadal dysgenesis may also be concerned when they do not develop menses or secondary sexual characteristics like their peers. Being able to produce offspring of our own is also a desire of many people in our society and being infertile and not being able to do that may cause a great deal of emotional turmoil. Proper fertility counseling, discussion of the patient’s options, and referral to the appropriate services are vital in caring for these patients with infertility. In patients with gonadal dysgenesis that contains Y chromosomal material, there is also an increased risk for the development of gonadoblastoma, dysgerminoma, teratoma, and choriocarcinoma, which requires removal of the gonads early on in life to prevent tumor formation.

Additionally, a large number of patients with gonadal dysgenesis will have other associated health problems. As seen in Turner syndrome there can be significant cardiac and renal abnormalities that will require assessment and management by a physician. Turner syndrome patients also commonly have short stature that will indicate treatment with growth hormone early on to decrease growth stunting. Many other possible conditions correlate with gonadal dysgenesis, and it is essential to keep an eye out for these complications and utilize multiple specialists to create a care team for each patient on an individual basis. Gonadal dysgenesis is a complex condition with associated symptoms spanning across many organ systems. Our understanding of gonadal dysgenesis is limited but improving with time. Clinicians must be familiar with gonadal dysgenesis so that when a patient appears with the clinical characteristics of the condition they do not go unnoticed and the patient can go on to receive the treatment they need to improve their development and decrease their mortality.


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Genetics, Gonadal Dysgenesis - Questions

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A young girl of short stature is screened for Turner syndrome, and her chromosomal makeup is found to be 45 X. If the monosomy is found to be paternal in origin, the spermatozoon involved was likely which one of the following?



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A young girl of 12 years of age comes into her provider's office for her health maintenance examination. The provider notes that she is overall healthy and has met all of her cognitive and motor milestones, but she has always been below average on her growth chart and is much shorter than other children her age. During today's visit, her mother notes that she has not yet started menses and has little to no breast development. What is the most likely finding on the karyotype of this girl?



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A young male is diagnosed with 46, XY gonadal dysgenesis. Which of the following is the best course of action to decrease his mortality going forward?



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A newborn infant girl is being examined in the newborn nursery. Which of the following parts of her presentation and examination would increase suspicion of Turner syndrome?



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A 16-year-old female presents to her primary care provider due to amenorrhea. On physical examination, she has minimal breast development and sparse pubic hair. Workup reveals elevated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. What finding is most likely expected to be present on pelvic imaging?



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Genetics, Gonadal Dysgenesis - References

References

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