Gonadal dysgenesis is classified as any congenital developmental disorder of the reproductive system characterized by a progressive loss of

primordial germ cells A germ cell is any cell that gives rise to the gametes of an organism that reproduces sexually. In many animals, the germ cells originate in the primitive streak and migrate via the gut of an embryo to the developing gonads. There, they undergo ...

on the developing

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

s of an embryo. One type of gonadal dysgenesis is the development of functionless,

fibrous tissue Connective tissue is one of the four primary types of animal tissue, a group of cells that are similar in structure, along with epithelial tissue, muscle tissue, and nervous tissue. It develops mostly from the mesenchyme, derived from the mesode ...

, termed streak gonads, instead of reproductive tissue. 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 produ ...

, resulting in hormonal failure that manifests as sexual infantism and

infertility In biology, infertility is the inability of a male and female organism to Sexual reproduction, reproduce. It is usually not the natural state of a healthy organism that has reached sexual maturity, so children who have not undergone puberty, whi ...

, 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 female, the testicles i ...

and

secondary sex characteristics A secondary sex characteristic is a physical characteristic of an organism that is related to or derived from its sex, but not directly part of its reproductive system. In humans, these characteristics typically start to appear during puberty ...

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

ovary The ovary () is a gonad in the female reproductive system that produces ova; when released, an ovum travels through the fallopian tube/ oviduct into the uterus. There is an ovary on the left and the right side of the body. The ovaries are end ...

testicle A testicle or testis ( testes) is the gonad in all male bilaterians, including humans, and is Homology (biology), homologous to the ovary in females. Its primary functions are the production of sperm and the secretion of Androgen, androgens, p ...

). Differentiation of the gonads requires a tightly regulated cascade of genetic, molecular and morphogenic events. At the formation of the developed gonad,

steroid A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes t ...

production influences local and distant receptors for continued morphological and

biochemical Biochemistry, or biological chemistry, is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology, ...

changes. This results in the

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

corresponding to the

karyotype A karyotype is the general appearance of the complete set of chromosomes in the cells of a species or in an individual organism, mainly including their sizes, numbers, and shapes. Karyotyping is the process by which a karyotype is discerned by de ...

(46,XX for females and 46,XY for males). Gonadal dysgenesis arises from a difference in signalling in this tightly regulated process during early

foetal development Prenatal development () involves 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 (; alternatively spelled aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek word ''()'', meaning "giving a reason for" (). More completely, etiology is the study of the causes, origin ...

and severity of the underlying causes.

Causes

* Pure gonadal dysgenesis 46,XX also known as

XX gonadal dysgenesis XX gonadal dysgenesis is a type of female hypogonadism in which the ovaries do not function to induce puberty in a person assigned female at birth, whose karyotype is 46,XX. Individuals with XX gonadal dysgenesis have normal-appearing external geni ...

* Pure gonadal dysgenesis 46,XY also known as

XY gonadal dysgenesis 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 go ...

Mixed gonadal dysgenesis 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 a ...

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, 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 a ...

Turner syndrome Turner syndrome (TS), commonly known as 45,X, or 45,X0,Also written as 45,XO. is a chromosomal disorder in which cells of females have only one X chromosome instead of two, or are partially missing an X chromosome (sex chromosome monosomy) lea ...

also known as

45,X Turner syndrome (TS), commonly known as 45,X, or 45,X0,Also written as 45,XO. is a chromosomal disorder in which cells of females have only one X chromosome instead of two, or are partially missing an X chromosome (sex chromosome monosomy) lead ...

or 45,X0 * Endocrine disruptions

Pathogenesis

46,XX gonadal dysgenesis

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

of 46,XX. Streak ovaries are present with non-functional tissues unable to produce the required sex steroid

oestrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three m ...

. 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 Feedback occurs when outputs of a system are routed back as inputs as part of a chain of cause and effect that forms a circuit or loop. The system can then be said to ''feed back'' into itself. The notion of cause-and-effect has to be handle ...

to the

anterior pituitary The anterior pituitary (also called the adenohypophysis or pars anterior) is a major Organ (anatomy), organ of the endocrine system. The anterior pituitary is the glandular, Anatomical terms of location#Usage in human anatomy, anterior lobe that t ...

to inhibit the secretion of FSH and LH. FSH and LH are secreted at elevated levels. Increased levels of these hormones will cause the body to not start

, not undergo

menarche Menarche ( ; ) is the first menstrual cycle, or first menstruation, menstrual bleeding, in female humans. From both social and medical perspectives, it is often considered the central event of female puberty, as it signals the possibility of fe ...

, and not develop

. If ovarian tissue is present and produces some amount of hormones, limited menstrual cycles can occur. 46,XX gonadal dysgenesis can manifest from a variety of causes. Interruption during ovarian development in

embryogenesis An embryo ( ) is the initial stage of development for a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male ...

can cause 46,XX gonadal dysgenesis with cases of changes 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 biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...

steroidogenic acute regulatory protein The steroidogenic acute regulatory protein, commonly referred to as StAR (STARD1), is a transport protein that regulates cholesterol transfer within the mitochondria, which is the rate-limiting step in the production of steroid hormones. It is ...

(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). Wit ...

production.

46,XY gonadal dysgenesis

46,XY gonadal dysgenesis is characteristic of

male hypogonadism Hypogonadism means diminished functional activity of the gonads—the testicles or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low est ...

with

46,XY. In

, the development of the male gonads is primarily 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 ...

located on the sex-determining region of the Y chromosome (

SRY 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 ...

). The male gonad is dependent on SRY and the

signalling pathways Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events. Proteins responsible for detecting stimuli are generally termed receptors, although in some cases the term ...

initiated to several other genes to facilitate

testis A testicle or testis ( testes) is the gonad in all male bilaterians, including humans, and is Homology (biology), homologous to the ovary in females. Its primary functions are the production of sperm and the secretion of Androgen, androgens, p ...

development. 46,XY gonadal dysgenesis can be caused by mutations in the

genes In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

involved in testis development such as SRY,

SOX9 Transcription factor SOX-9 is a protein that in humans is encoded by the ''SOX9'' gene. Function SOX-9 recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding domain, DNA-binding proteins. It is expressed by ...

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-rich ...

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

penis A penis (; : penises or penes) is a sex organ through which male and hermaphrodite animals expel semen during copulation (zoology), copulation, and through which male placental mammals and marsupials also Urination, urinate. The term ''pen ...

and

scrotum In most terrestrial mammals, the scrotum (: scrotums or scrota; possibly from Latin ''scortum'', meaning "hide" or "skin") or scrotal sac is a part of the external male genitalia located at the base of the penis. It consists of a sac of skin ...

. ''Genital Undermasculinization'' is the technical term for partial of complete undifferentiated genitallia in individuals with an

SRY gene 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 ...

In utero The uterus (from Latin ''uterus'', : uteri or uteruses) or womb () is the organ in the reproductive system of most female mammals, including humans, that accommodates the embryonic and fetal development of one or more fertilized eggs until bir ...

, all fetuses are anatomically undifferentiated which are then differentiated via androgen's and SRY activation. Full undermasculinization results in a fully developed

vulva In mammals, the vulva (: vulvas or vulvae) comprises mostly external, visible structures of the female sex organ, genitalia leading into the interior of the female reproductive tract. For humans, it includes the mons pubis, labia majora, lab ...

with testicles inside the body where the ovaries usually are, which is caused by conditions such as

complete androgen insensitivity syndrome 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 individual ...

. In

5α-Reductase 2 deficiency 5α-Reductase 2 deficiency (5αR2D) is an autosomal recessive condition caused by mutations impairing the function of ''SRD5A2'', a gene located on chromosome 2 and encoding the enzyme 5α-reductase type 2 (5αR2). 5αR2 is expressed in specific ...

, individuals are born with normal female genitalia, however, during puberty, male differentiation and

spermatogenesis Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testicle. This process starts with the Mitosis, mitotic division of the stem cells located close to the basement membrane of ...

occurs. Partial genital undermasculinization can occur if the body has a partial resistance to androgens, or if genital development is blocked, undermasculization can also be induced by certain drugs and

hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...

s. The overall intensity of undermasculinization can manifest itself in

hypospadias Hypospadias is a common malformation in fetal development of the penis in which the urethra does not open from its usual location on the head of the penis. It is the second-most common birth defect of the male reproductive system, affecting about ...

. The surgical assignment of newborns with ambiguous genitalia to a binary sex for cosmetic purposes is considered a

human rights violation Human rights are universally recognized Morality, moral principles or Social norm, norms that establish standards of human behavior and are often protected by both Municipal law, national and international laws. These rights are considered ...

. 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-sti ...

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

testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...

and

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

production. Lowered levels of testosterone and anti-Müllerian hormone disrupts the development of

Wolffian ducts The mesonephric duct, also known as the Wolffian duct, archinephric duct, Leydig's duct or nephric duct, is a paired organ that develops in the early stages of embryonic development in humans and other mammals. It is an important structure that pl ...

and internal genitalia that are key to male reproductive tract development. The absence of the steroid hormones commonly associated with males drives

Müllerian duct The paramesonephric ducts (or Müllerian ducts) are paired ducts of the embryo in the reproductive system of humans and other mammals that run down the lateral sides of the genital ridge and terminate at the sinus tubercle in the primitive uroge ...

development and promotes the development of female genitalia, if anti-Müllerian hormone is suppressed or the body is insensitive,

persistent Müllerian duct syndrome Persistent Müllerian duct syndrome (PMDS) is the presence of Müllerian duct derivatives (fallopian tubes, uterus, and/or the upper part of the vagina) in what would be considered a genetically and otherwise physically normal male. In humans, ...

occurs when the individual has partial female reproductive, and partial male reproductive organs. Gonadal streaks can replace the tissues of 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 persons.

Mixed gonadal dysgenesis

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

aneuploidy Aneuploidy is the presence of an abnormal number of chromosomes in a cell (biology), cell, for example a human somatic (biology), somatic cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more plo ...

and mosaicism of the

Y chromosome The Y chromosome is one of two sex chromosomes in therian mammals and other organisms. Along with the X chromosome, it is part of the XY sex-determination system, in which the Y is the sex-determining chromosome because the presence of the ...

. Mixed gonadal dysgenesis is the presence of two or more germ line 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, 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 a ...

are highly variable with

asymmetry Asymmetry is the absence of, or a violation of, symmetry (the property of an object being invariant to a transformation, such as reflection). Symmetry is an important property of both physical and abstract systems and it may be displayed in pre ...

gonadal development The development of the gonads is part of the prenatal development, prenatal development of the reproductive system and ultimately forms the testicles in males and the ovaries in females. The immature ova originate from cells from the dorsal endod ...

of testis and streak gonad, accounted for by the percentage of cells expressing XY genotype. The dysgenic testis can have an amount of functional tissue which can produce a level of testosterone, which causes 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 three main types: "reciprocal", "nonreciprocal" and "Robertsonian" transloc ...

, or migration diffenernce of paired chromosomes during

cell division Cell division is the process by which a parent cell (biology), 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 eukar ...

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

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 chromosomes in many organisms, including mammals, and is found in both males and females. It is a part of the XY sex-determination system and XO sex-determination system. The X chromosome was named for its u ...

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

meiosis Meiosis () is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, the sperm or egg cells. It involves two rounds of division that ultimately result in four cells, each with only one c ...

signalling to

germ cells A germ cell is any cell that gives rise to the gametes of an organism that reproduces sexually. In many animals, the germ cells originate in the primitive streak and migrate via the gut of an embryo to the developing gonads. There, they undergo ...

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 I ...

and monosomy X from not occurred separation of chromosomes in either the parental

gamete A gamete ( ) is a Ploidy#Haploid and monoploid, haploid cell that fuses with another haploid cell during fertilization in organisms that Sexual reproduction, reproduce sexually. Gametes are an organism's reproductive cells, also referred to as s ...

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 Amenorrhea or amenorrhoea is the absence of a menstrual period in a female organism who has reached reproductive age. Physiological states of amenorrhoea are most commonly seen during pregnancy and lactation (breastfeeding). In humans, it is wher ...

hypergonadotropic hypogonadism 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 ...

, streak gonads,

, and failure to develop

. Turner syndrome is usually 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 (physical form and structure), its developmental processes, its biochemical and physiological propert ...

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 edema, swelling caused by a compromised lymphatic system. The lymphatic system functions as a critical portion of the body's immune system and returns inters ...

at birth. Comorbidities include

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

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,

diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...

, and low

thyroid hormone File:Thyroid_system.svg, upright=1.5, The thyroid system of the thyroid hormones triiodothyronine, T3 and T4 rect 376 268 820 433 Thyroid-stimulating hormone rect 411 200 849 266 Thyrotropin-releasing hormone rect 297 168 502 200 Hypothalamus r ...

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 n ...

interfere with the

endocrine system The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant Organ (biology), organs. In vertebrat ...

and

hormones A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physiology and behavior. Hormones a ...

. Hormones are critical for the common events in embryogenesis to occur.

Foetal development Prenatal development () involves 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 Cellular differentiation is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellula ...

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 endocrine system Congenital disorders of genital organs Intersex topics Intersex healthcare Intersex variations Rare diseases Sex differences in humans