Gonadal dysgenesis is classified as any congenital developmental disorder of the reproductive system in the male or female. It is the atypical development of the

gonads A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sper ...

in an embryo, with reproductive tissue replaced with functionless,

fibrous tissue Fiber or fibre (from la, fibra, links=no) is a natural or artificial substance that is significantly longer than it is wide. Fibers are often used in the manufacture of other materials. The strongest engineering materials often incorporate ...

, termed streak gonads. Streak gonads are a form of

aplasia Aplasia (; from Greek ''a'', "not", "no" + ''plasis'', "formation") is a birth defect where an organ or tissue is wholly or largely absent. It is caused by a defect in a developmental process. Aplastic anemia is the failure of the body to produc ...

, resulting in hormonal failure that manifests as sexual infantism and infertility, with no initiation of

puberty Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a bo ...

and

secondary sex characteristics Secondary sex characteristics are features that appear during puberty in humans, and at sexual maturity in other animals. These characteristics are particularly evident in the sexually dimorphic phenotypic traits that distinguish the sexes of a s ...

. Gonadal development is a genetically controlled process by the chromosomal sex ( XX or XY) which directs the formation of the gonad ( ovary or

testis A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testostero ...

). Differentiation of the gonads requires a tightly regulated cascade of genetic, molecular and morphogenic events. At the formation of the developed gonad, steroid production influences local and distant receptors for continued morphological and biochemical changes. This results in the appropriate

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological pr ...

corresponding to the karyotype (46,XX for females and 46,XY for males). Gonadal dysgenesis arises from the failure of signalling in this tightly regulated process during early

foetal development Prenatal development () includes the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal deve ...

. Manifestations of gonadal dysgenesis are dependent on the

aetiology Etiology (pronounced ; alternatively: aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek (''aitiología'') "giving a reason for" (, ''aitía'', "cause"); and ('' -logía''). More completely, e ...

and severity of the underlying defect.

Causes

* Pure gonadal dysgenesis 46,XX also known as XX gonadal dysgenesis * Pure gonadal dysgenesis 46,XY also known as XY gonadal dysgenesis *

Mixed gonadal dysgenesis 45,X/46,XY mosaicism, also known as X0/XY mosaicism and mixed gonadal dysgenesis,

also known as partial gonadal dysgenesis, and

45,X/46,XY mosaicism 45,X/46,XY mosaicism, also known as X0/XY mosaicism and mixed gonadal dysgenesis,

Turner syndrome Turner syndrome (TS), also known as 45,X, or 45,X0, is a genetic condition in which a female is partially or completely missing an X chromosome. Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low hair ...

also known as

45,X Turner syndrome (TS), also known as 45,X, or 45,X0, is a genetic condition in which a female is partially or completely missing an X chromosome. Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low hairl ...

or 45,X0 * Endocrine disruptions

Pathogenesis

46,XX gonadal dysgenesis

46,XX gonadal dysgenesis is characteristic of female hypogonadism with a karyotype of 46,XX.

Streak ovaries Gonadal dysgenesis is classified as any congenital developmental disorder of the reproductive system in the male or female. It is the atypical development of the gonads in an embryo, with reproductive tissue replaced with functionless, fibrous ti ...

are present with non-functional tissues unable to produce the required sex steroid

oestrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...

. Low levels of oestrogen effect the

HPG axis HPG may refer to: * Huppuguda railway station, in Hyderabad, India * Hypothalamic–pituitary–gonadal axis * People's Defence Forces (Kurdish: '), the armed wing of the Kurdistan Workers' Party * Shennongjia Hongping Airport, in Hubei, China * ...

with no feedback to the anterior pituitary to inhibit the secretion of FSH and LH. FSH and LH are secreted at abnormal elevated levels. Improper levels of these hormones will cause a failure to initiate

, undergo menarche, and develop

. If sufficient functional ovarian tissue is present, limited

menstrual cycles The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eggs ...

can occur. The pathogenesis of 46,XX gonadal dysgenesis is unclear, as it can manifest from a variety of dysregulations. Interruption during ovarian development in embryogenesis can cause 46,XX gonadal dysgenesis with cases of abnormalities in the

FSH receptor The follicle-stimulating hormone receptor or FSH receptor (FSHR) is a transmembrane receptor that interacts with the follicle-stimulating hormone (FSH) and represents a G protein-coupled receptor (GPCR). Its activation is necessary for the horm ...

and mutations in steroidogenic acute regulatory protein (StAR protein) which regulates

steroid hormone A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into two classes: corticosteroids (typically made in the adrenal cortex, hence ''cortico-'') and sex steroids (typically made in the gonads or placenta). Withi ...

production.

46,XY gonadal dysgenesis

46,XY gonadal dysgenesis is characteristic of male hypogonadism with karyotype 46,XY. In embryogenesis, the development of the male gonads is controlled by the

testis determining factor Sex-determining region Y protein (SRY), or Testis-determining factor (TDF), is a DNA-binding protein (also known as gene-regulatory protein/transcription factor) encoded by the ''SRY'' gene that is responsible for the initiation of male sex d ...

located on the sex-determining region of the Y chromosome ( SRY). The male gonad is dependent on SRY and the signalling pathways initiated to several other genes to facilitate

development. The

of 46,XY gonadal dysgenesis can be caused by mutations in the genes involved in testis development such as SRY, SOX9,

WT1 Wilms tumor protein (WT33) is a protein that in humans is encoded by the ''WT1'' gene on chromosome 11p. Function This gene encodes a transcription factor that contains four zinc finger motifs at the C-terminus and a proline / glutamine-ric ...

, SF1, and DHH. If a single or combination of these genes are mutated or deleted, downstream signalling is disrupted, leading to malformation of

male external genitalia A sex organ (or reproductive organ) is any part of an animal or plant that is involved in sexual reproduction. The reproductive organs together constitute the reproductive system. In animals, the testis in the male, and the ovary in the female, ...

. SRY acts on gene SOX9 which drives

Sertoli cell Sertoli cells are a type of sustentacular "nurse" cell found in human testes which contribute to the process of spermatogenesis (the production of sperm) as a structural component of the seminiferous tubules. They are activated by follicle-stimu ...

formation and testis differentiation. An absence in SRY causes SOX9 to not be expressed at the appropriate time or concentration, leading to a deficiency in

testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristi ...

and

anti-Müllerian hormone Anti-Müllerian hormone (AMH), also known as Müllerian-inhibiting hormone (MIH), is a glycoprotein hormone structurally related to inhibin and activin from the transforming growth factor beta superfamily, whose key roles are in growth differen ...

production. Inadequate levels of testosterone and anti-Müllerian hormone disrupts the development of Wolffian ducts and internal genitalia that are key to male reproductive tract development. The lack of the male associated steroid hormones drives

Müllerian duct Paramesonephric ducts (or Müllerian ducts) are paired ducts of the embryo that run down the lateral sides of the genital ridge and terminate at the sinus tubercle in the primitive urogenital sinus. In the female, they will develop to form the fal ...

development and promotes the development of female genitalia. Gonadal streaks replace the tissues of the testes, resembling ovarian stroma absent of follicles. 46,XY gonadal dysgenesis can remain unsuspected until delayed pubertal development is observed. Approximately 15% of cases of 46,XY gonadal dysgenesis carry ''de novo'' mutations in the SRY gene, with an unknown causation for the remaining portion of 46,XY gonadal dysgenesis patients.

Mixed gonadal dysgenesis

Mixed gonadal dysgenesis, also known as X0/XY mosaicism or partial gonadal dysgenesis, is a sex development disorder associated with sex chromosome

aneuploidy Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more complete sets of chromosomes. A cell with any ...

and mosaicism of the

Y chromosome The Y chromosome is one of two sex chromosomes (allosomes) in therian mammals, including humans, and many other animals. The other is the X chromosome. Y is normally the sex-determining chromosome in many species, since it is the presence or abse ...

. Mixed gonadal dysgenesis is the presence of two or more

germ line In biology and genetics, the germline is the population of a multicellular organism's cells that pass on their genetic material to the progeny (offspring). In other words, they are the cells that form the egg, sperm and the fertilised egg. They ...

cells. The degree of development of the male reproductive tract is determined by the ratio of germ line cells expressing the XY genotype. Manifestations of

mixed gonadal dysgenesis 45,X/46,XY mosaicism, also known as X0/XY mosaicism and mixed gonadal dysgenesis,

are highly variable with asymmetry in gonadal development of testis and streak gonad, accounted for by the percentage of cells expressing XY genotype. The dysgenic testis can have adequate functional tissue to produce satisfactory levels of testosterone to cause masculinisation. Mixed gonadal dysgenesis is poorly understood at the molecular level. The loss of the

can occur from deletions,

translocations In genetics, chromosome translocation is a phenomenon that results in unusual rearrangement of chromosomes. This includes balanced and unbalanced translocation, with two main types: reciprocal-, and Robertsonian translocation. Reciprocal translo ...

, or

migration Migration, migratory, or migrate may refer to: Human migration * Human migration, physical movement by humans from one region to another ** International migration, when peoples cross state boundaries and stay in the host state for some minimum le ...

failure of paired chromosomes during

cell division Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there ar ...

. The chromosomal loss results in partial expression of the SRY gene, giving rise to abnormal development of the

reproductive tract The reproductive system of an organism, also known as the genital system, is the biological system made up of all the anatomical organs involved in sexual reproduction. Many non-living substances such as fluids, hormones, and pheromones are al ...

and altered hormone levels.

Turner syndrome

, also known as 45,X or 45,X0, is a

chromosomal abnormality A chromosomal abnormality, chromosomal anomaly, chromosomal aberration, chromosomal mutation, or chromosomal disorder, is a missing, extra, or irregular portion of chromosomal DNA. These can occur in the form of numerical abnormalities, where ther ...

characterised by a partial or completely missing second

X chromosome The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex ...

, giving a chromosomal count of 45, instead of the typical count of 46 chromosomes. Dysregulation in

meiosis Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately r ...

signalling to

germ cells Germ or germs may refer to: Science * Germ (microorganism), an informal word for a pathogen * Germ cell, cell that gives rise to the gametes of an organism that reproduces sexually * Germ layer, a primary layer of cells that forms during embryo ...

during embryogenesis may result in

nondisjunction Nondisjunction is the failure of homologous chromosomes or sister chromatids to separate properly during cell division (mitosis/meiosis). There are three forms of nondisjunction: failure of a pair of homologous chromosomes to separate in meiosis ...

and monosomy X from separation failure of chromosomes in either the parental

gamete A gamete (; , ultimately ) is a haploid cell that fuses with another haploid cell during fertilization in organisms that reproduce sexually. Gametes are an organism's reproductive cells, also referred to as sex cells. In species that produce ...

or during early embryonic divisions. The

of Turner syndrome

can be the result of

haploinsufficiency Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms, in which a single copy of the wild-type allele at a locus in heterozygous combination with a variant allele is insufficient to produce the wild-type ...

, where a portion of critical genes are rendered inactive during embryogenesis. Normal ovarian development requires these vital regions of the X chromosome that are inactivated. Clinical manifestation include primary amenorrhea,

hypergonadotropic hypogonadism Hypergonadotropic hypogonadism (HH), also known as primary or peripheral/gonadal hypogonadism or primary gonadal failure, is a medical condition, condition which is characterized by hypogonadism which is due to an impaired response of the gonads to ...

, streak gonads, infertility, and failure to develop

. Turner syndrome is not diagnosed until a delayed onset of

with Müllerian structures found to be in infantile stage. Physical

phenotypic In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...

characteristics include

short stature Short stature refers to a height of a human which is below typical. Whether a person is considered short depends on the context. Because of the lack of preciseness, there is often disagreement about the degree of shortness that should be called ' ...

, dysmorphic features and

lymphedema Lymphedema, also known as lymphoedema and lymphatic edema, is a condition of localized swelling caused by a compromised lymphatic system. The lymphatic system functions as a critical portion of the body's immune system and returns interstitial fl ...

at birth.

Comorbidities In medicine, comorbidity - from Latin morbus ("sickness"), co ("together"), -ity (as if - several sicknesses together) - is the presence of one or more additional conditions often co-occurring (that is, concomitant or concurrent) with a primary ...

include

heart defects A congenital heart defect (CHD), also known as a congenital heart anomaly and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular ...

vision Vision, Visions, or The Vision may refer to: Perception Optical perception * Visual perception, the sense of sight * Visual system, the physical mechanism of eyesight * Computer vision, a field dealing with how computers can be made to gain und ...

and

hearing problems Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spoken la ...

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...

, and low thyroid hormone production.

Endocrine disruptions

Endocrine disruptors Endocrine disruptors, sometimes also referred to as hormonally active agents, endocrine disrupting chemicals, or endocrine disrupting compounds are chemicals that can interfere with endocrine (or hormonal) systems. These disruptions can cause ca ...

interfere with the

endocrine system The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neu ...

and hormones. Hormones are critical for the correct events in embryogenesis to occur.

Foetal development Prenatal development () includes the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal deve ...

relies on the proper timing of the delivery of hormones for cellular differentiation and maturation. Disruptions can cause sexual development disorders leading to gonadal dysgenesis.

Diagnosis

Management

History

Turner syndrome was first described independently by Otto Ulrich in 1930 and Henry Turner in 1938. 46,XX pure gonadal dysgenesis was first reported in 1960. 46,XY pure gonadal dysgenesis, also known as Swyer syndrome, was first described by Gim Swyer in 1955.

References

External links

{{DEFAULTSORT:Gonadal Dysgenesis Congenital disorders of female genital organs Intersex variations Rare diseases