The Intersex Genetics Masterpost
Everything You Could Ever Want to Know, Written by Someone with CAH
I’ll start this off by explaining what intersex organizations have meant when they say “spectrum of sex,” “diversity of biological sex,” or “binary ideas of sex.” These terms have been muddied and coopted to fit other groups’ campaigning without care for what they originally meant.
When we say sex is diverse and does not fit into a binary, it means that there is more than one phenotype for the male sex and more than one phenotype for the female sex. Both a male who is not intersex and someone with AIS, an XY condition that makes the body unable to use androgens and therefore no male development occurs giving the person a female phenotype, are still male. Male encompasses the spectrum of XY sexual development between non-intersex male and completely androgen-free males with female phenotypes like AIS and XY lipoid CAH people. Male also includes Swyer Syndrome, where the coding for the hormone that switches uterus development to testes development is mutated and causes uterine development instead.
As for females, you have non-intersex females and you can have females with phenotypes like mine with CAH or a male phenotype like De La Chapelle Syndrome (XX condition where during spermatogenesis a portion of a Y chromosome is accidentally fused onto the arm of the gamete’s intended X). That gives us a spectrum of the way females can be.
There is no “binary” way of being male because males can have penises and functioning testes (non-intersex), clitoromegaly and internal testes (PAIS), or a female-appearing vulva and regular clitoris size with internal testes (AIS). There are even males with uteri in the case of Swyer Syndrome. There is no “binary” way of being female because of the same things.
The “spectrum of sex” is where we overlap phenotypes between two sexes. A non-intersex female will look phenotypically the same as someone with AIS. A non-intersex male will look phenotypically the same as someone with De La Chapelle Syndrome. And I, an intersex female with androgen exposure, will look like an intersex male with PAIS who has had only partial of general male androgen exposure. A side note on that last part, for several years I thought Pidgeon Pagonis had CAH too based on the genitalia descriptions they gave because it was all the same with me. I didn’t know any better until I joined the intersex Discord and the topic came up.
However, while there are not dichotomous ways of being male or female, we know that everyone is either male or female for an important reason: the only reason ours or any species has biological sex is to add different angles and gametes to sexual reproduction. In humans, there are only two options: to make and develop a system to use ova for pregnancy, or to make and develop a system to use spermatozoa for impregnation. No intersex person produces the opposite sex’s gamete or has the full and functioning system of the opposite sex to use that gamete. Most of us are infertile.
If intersex people represented a biological sex other than male or female, we would expect most people to be intersex and few to be male or female. This is like any other thing in statistics: opposite-end extremes are the rarest, while roughly 95% falls in the middle-range, just like a bell curve.
We also know that truly being intersex (having a major difference of congenital reproductive development, not PCOS, hormonal differences, or general NCAH) is not 1.7% as many “activists” love to boast about, comparing to red hair and green eyes. The true statistic is about .0667% of the population having an intersex condition.
What is “intersex”?
Intersex defined as a congenital physical abnormality of the reproductive system’s development. I.E., MRKH is intersex because it causes underdevelopment or absence of the uterus and external genitals, classic CAH is intersex because it causes overdevelopment of the clitoris that leads to atrophy of the vagina/cervix and change in location of the urethra.
PCOS is like nonclassical CAH with regards to intersex; the vast majority of all NCAH cases do not present reproductive physical differences from birth and so aren’t classified as intersex. A few cases of NCAH are severe enough to affect fetal development and those would be intersex. That doesn’t happen with PCOS because PCOS does not start presenting until pubarche when the ovaries begin responding to LH and FSH.
The assumption that PCOS is inherently intersex comes from the idea that intersex is any change in cosmetic appearance from the average of male or female, or that biological sex is a spectrum determined by sex steroid levels and those with abnormal levels for their sex are not dimorphic but intersex–a misinterpretation of what intersex is. A lot of people also think that when doctors describe PCOS as causing “high testosterone” that that level is comparable to virilizing female intersex disorders. But high testosterone for PCOS is not remotely near the range of what occurs for CAH and does not cause virilization further than hirsutism, oiliness, acne, balding, and in very rare instances late-onset minor clitoromegaly. On the hand of CAH, facial structure can become virilized, beard growth is fuller rather than sparse like hirsutism, the voice deepens, and the body will default to a muscular, more male-looking shape even without exercise to do so.
In utero exposure to androgens for CAH girls is also unlike PCOS because it causes our labia to grow, redden, gain rugae, close a little bit to fully (the latter if you have the most severe form of CAH), and relocate the urethra and vagina sometimes overlapping the two into the same canal. That’s the intersex symptom of CAH: the complete makeover to the reproductive system starting from the moment of development.
PCOS and other non-extreme hormonal imbalances aren’t a cause for that sort of development and therefore would not be intersex.
With that descriptor out of the way, onward from here we will be looking at each intersex variant, how it arises, what sex, why it belongs solely to that sex, the frequency of occurrence etc. Everything will be linked to sources. Some sources may overlap because I’m trying to keep each entry consistent but the information is on the same page as another part’s source, like finding the occurrence frequency. Some links will be from MedScape, which has a free registration to view more than a few links but the sources there are good–I will remain skimpy with using these links because of the needing to register.
If you click a link to one of the diseases associated with varying gene’s mutations for different intersex conditions and cannot find how it is tied to that mutation of the gene, you can open that gene’s protein or enzyme UniProt page as linked in its description in this post and go to the section for Pathology & Biotech. All diseases associated with intersex gene mutations that I have sourced can be found there.
Readers, be forewarned that there are links to images including nude bodies, genitalia and internal organs. Among links there are descriptions of medical suffering and sometimes even death of intersex patients. They are not outright shown, but clicking on certain links will bring them up.
For any further exploration on the coding, expression, function, and diseases caused by mutation of each gene, please search the name of the gene here at Atlas Genetics Oncology or the Domain Mapping of Disease Mutations Database. They are both extremely good resources. This post primarily uses UniProt for links to these types of information on genes.
As a preface to the tremendous materials further in this post, here you can find a very generalized PDF that includes important sections such as Table 4: Risk of Germ Cell Malignancy According to Diagnosis, Table 5: Genes Known to be Involved in Disorders of Sex Development 46, XY, and Table 6: Genes Known to be Involved in Disorders of Sex Development 46, XX. This PDF draws from 92 peer-reviewed, accredited sources.
Aside from general scientific information, I’m including pictures of intersex people because everyone needs to see that we look just like the rest of you when you cross us on the streets. We’re normal people, too.
And with that, let’s get the ball rolling.
(21-hydroxlyase deficiency, 11-beta hydroxylase deficiency, 17-alpha hydroxylase deficiency, P450 oxidoreductase deficiency / POR deficiency (PORD, Antley-Bixler Syndrome), stAR deficiency / STARD1 / lipoid CAH, and 3-beta hydroxysteroid dehydrogenase deficiency)
Rate of Occurrence: 1 in 13,000 (does not include instances of NCAH that do not produce the congenital reproductive anomalies that are considered intersex; most of this number comes from classic 21-hydroxylase deficiency, which is 95–99% of all CAH cases)
CYP21A2 — locus 6p21.33; codes for enzyme 21-hydroxylase which converts progesterone to 11-deoxycortisol, a precursor of cortisol and aldosterone. Associated exclusively with 21-hydroxylase deficiency type CAH. There is a salt-wasting and simple virilizing variety, salt-wasting being mutations resulting in no enzyme function, and simple virilizing coming from mutations resulting in severe loss of enzyme function but retaining some.
*Mortality is only listed here for 21-hydroxylase type CAH as the other forms are extremely rare but equally as deadly.
— Endocrine Profile: high progesterone leading to high androgens, low to no cortisol and (exclusive to salt-wasters) low to no aldosterone
— Intersex: Only females are intersex. Due to increased androgens, specifically due to testosterone and dihydrotestosterone (DHT) exposure in utero. Growth of the clitoris and atrophy of the vagina occur. The urethra may become displaced toward or into the clitoris in more severe forms, and in the most severe the vagina becomes fused with the urethra*. Males simply have larger penises than average and may grow body and facial hair earlier than their peers. Females still have all Mullerian structures (ovaries, uterus, cervix) but may be infertile from inability to ovulate.
*Note that in this image, I through V all have uteri–as they are all female CAH patients. The male on the far right is only shown as comparison. While V may seen “male” as drawn on the image at the bottom, the “balls” shown are actually empty skin sacs as there are no testes to descend. This type of CAH may look intense as an infant but we grow into our genitals and they look more like this as an adult.
CYP11B1 — locus 8q21.3; codes for enzyme 11-beta hydroxylase which converts 11-deoxycorticosterone into corticosterone and converts 11-deoxycortisol into cortisol. Associated exclusively with 11-beta-hydroxylase deficiency type CAH (second information link).
— Endocrine Profile: high progesterone leading to high androgens, low to no cortisol and aldosterone
— Intersex: Only females are intersex. As with 21-hydroxylase deficiency type CAH, androgens are in excess and cause the same phenotypical appearances in females. Males, again, may experience only an increase in penis size and earlier age of pubarche with regards to sexual physical changes.
CYP17A1 — locus 10q24.32; codes for enzyme 17-alpha hydroxylase (alternative link) which converts pregnenolone to 17-hydroxypregnenolone and progesterone to 17-hydroxyprogesterone. The gene also influences 17- and 20-lyase activity, which converts 17-hydroxypregnenolone to dehydroepiandrosterone (DHEA). Associated exclusively with 17-alpha-hydroxylase deficiency type CAH.
— Endocrine Profile: very low to no androgens and estrogens, cortisol production is impaired but glucocorticoids and corticosterone are high
— Intersex: Only males are intersex. This form of CAH is androgen-suppressing, and while females do not need androgens to develop female phenotype, males need androgens to develop a male phenotype. Males may range from having hypospadias to having a complete female phenotype. They will always have testes, rather internal or external. The vagina, as they produce anti-Mullerian hormone and so produce Wolffian (male) rather than Mullerian (female) internal organs, will be blind (blind vaginal pouch/pocket). Females may experience “sexual infantilism,” characterized by lack of body hair and breast development.
HSD3B2 — locus 1p12; codes for enzyme 3-beta hydroxysteroid dehydrogenase (alternative link), which functions both in the gonads and adrenals, and is key in the production of cortisol, aldosterone, androgens, and estrogens among others. Associated exclusively with 3-beta hydrosxysteroid dehydrogenase deficiency type CAH.
— Mutations (it’s one of those pay-to-view things but it’s the only one I could find for this rare disorder)
— Endocrine Profile: low androgens, estrogens, cortisol and aldosterone
— Intersex: The same as with 17-alpha-hydroxylase type CAH, only males are intersex.
POR — locus 7q11.23; codes for the enzyme P450 oxidoreductase, a critical enzyme required for the proper functioning of more than 50 enzymes in the cytochrome P450 subfamily (involved in almost every step of adrenal steroidogenesis). Associated exclusively with POR deficiency type CAH, which is also called PORD or Antley-Bixler Syndrome.
— Endocrine Profile: extremely varied depending on which mutation has occurred and the extent of what it can do in the steroidogenesis pathways and skeletal development
— Intersex: Children of either sex can be born with normal genitals for their sex or ambiguous genitalia depending on the severity and range of the P450 oxidoreductase deficiency. All males retain Wollfian structures regardless of genitals and do not produce ova. All females retain Mullerian structures regardless of genitals and do not produce spermatozoa.
STAR — locus 8p11.23; codes for steroidal acute regulatory protein (stAR), the enzyme that converts cholesterol to pregnenolone. Without functioning stAR, no hormonal production in the adrenals or gonads can occur. Associated exclusively with lipoid CAH.
— Endocrine Profile: Because stAR is needed to bring cholesterol to the gonads and adrenals to form any other hormone, these patients have no steroids and that is referred to as “global silencing.” There is an extremely high buildup of cholesterol and adrenocorticotropic hormone (ACTH) and no cortisol, aldosterone, or sex steroids.
— Intersex: Only males are intersex. Because loss of stAR prevents any activity in the testes, no androgens are released and male development does not take place. Males do not develop Mullerian structures as there are no mutations obstructing anti-Mullerian hormone; they retain Wolffian structures and the testes are internal, and, like the adrenals, build up too much cholesterol and are broken down from gondal tissue into masses of lipids. As there are no Mullerian structures, males have a blind vagina.
— Medical Slide (generalized, does not focus on one specific type)
Congenital Adrenal Hyperplasia is the most common variant of intersex. There are so many types of CAH listed because it is an umbrella term for genetic mutations resulting in affected ability to create adrenal hormones, causing hyperplasia (overgrowth) of the adrenal glands as they overwork failing to produce the hormones.
CAH is autosomal recessive. That means it is unrelated to the sex chromosomes, and to get it you must inherit a mutated allele from both of your parents. Having only one mutated allele results in a healthy carrier of the disorder.
I have previously written a Congenital Adrenal Hyperplasia masterpost.
All patients with CAH require lifelong and tediously-managed corticosteroid replacement. Without replacement, we will die of adrenal crisis like Addison’s patients. Daily, if our medication is imbalanced, we can experience symptoms of low cortisol if our doses are too low or too spread out (we need three a day) or symptoms of high cortisol if our doses are too high or frequent.
— “Table 2 illustrates the ethnic diversity of CAH genotypes. We note that certain genotypes are more frequent in specific ethnic groups. For example, the I2G/I2G genotype is more prevalent in the Middle Eastern population. As noted before, the exon 7 V281L mutation associated with NC CAH is very frequent in the Ashkenazi Jewish population. We also find that CAH is rare in Asian, African American, and East Indian populations in this cohort.”
— “The highest incidence of lipoid CAH is in Japan and Korea, where the heterozygous carrier frequency is estimated to be about 1 in 300 [154,169]. The estimated number of affected newborns is 1 in every 250 000–300 000, and the expected total number of patients in Japan and Korea is about 500 patients.”
(Generalized as AIS, but broken down into two groups: Complete Androgen Insensitivity Syndrome (CAIS), caused by nullifying mutations, and Partial Androgen Insensitivity Syndrome (PAIS) / Reifenstein Syndrome, a “nonclassical” version that only partially obstructs gene function.)
Rate of Occurrence: 1 in 13,000 for CAIS and 1 in 130,000 for PAIS
AR — locus Xq12; responsible for proper functioning of the body’s androgen receptor proteins. Specifically, the powerful dihydrotestosterone (DHT) receptor, which has three times the androgenic potency of testosterone but is not anabolic (inducing gains of muscle mass).
Complete Androgen Insensitivity Syndrome (CAIS)
— Endocrine Profile: Very high androgen levels as the body will try to produce more when it notices it has no reaction to them. Eventually these androgens are picked up by the aromatase enzyme and converted into estrogens, causing female secondary sex characteristics. Patients have high concentration of follicle stimulating hormone (FSH) that intends to stimulate the testes to produce more androgens, again in response to the body’s inability to process them.
— Intersex: Only males are intersex. Lack of androgen reaction prevents male development from occurring and aromatization of androgens into estrogens allows for pubertal female secondary sex characteristic development to occur. There are no mutations obscuring production and use of anti-Mullerian hormone, so Mullerian (female) structures are not formed and Wolffian (male) structures develop, leading to testes. Sometimes one or both testes may descend, even in CAIS patients. The vagina is always blind as there are no Mullerian structures. Neither CAIS nor PAIS patients will have menstruation (as with all other XY intersex cases except for Swyer Syndrome) as they do not have uteri or ovaries.
It is hypothesized that a female could not inherit AIS at all, as it is X-linked it requires a copy from each parents, and affected males only have one X to give and most AIS patients are sex-reversed and sterile. A female could only inherit very mild PAIS from a father that had almost no signs of it, and even then she would only have very mild PAIS herself. She would still develop Mullerian structures, produce and use ova, and operate just like any other non-intersex female with the exception of potentially having less body and pubic hair due to some insensitivity to androgens.
Partial Androgen Insensitivity Syndrome (PAIS) / Reifenstein Syndrome
— OMIM Entry (same link as above)
— Endocrine Profile: Similar to CAIS but slightly less extreme. Patients with very mild PAIS will be even less profound than other cases of PAIS.
— Intersex: Range from almost non-intersex looking male with micropenis and lack of facial/body hair growth, to having hypospadias, to having clitoromegaly and labioscrotal folds that looks just like CAH girls’ but with a blind vagina, to having a common-sized clitoris with no labioscrotal folds and a blind vagina. As with CAIS, only males are affected and it is only hypothesized that a female could inherit it, and if so it is known that she would have no intersex variation.
— Complications associated with either form of AIS*:
Internal Testes May Become Cancerous / Have Malignant Tumors (only in some cases; do not immediately jump to removal of healthy tissues as that will require the patient to live on pharmaceutically-substituted sex steroids for the rest of their life for bone and heart health maintenance)
Shallow Vagina (due to being blind as not connected to a uterus; this is a long article but searching ‘shallow’ in it will get you to the point; can cause pain during penetrative sex)
Need for HRT for Bone and Heart Health (if testes are removed or if the patient does not have high enough estrogen levels)
*Note that not all patients with AIS may have these, much like some Turner Syndrome patients are able to develop ovaries while others do not.
— In-Depth View and Treatment (both varieties of AIS)
Rate of Occurrence: 1 in 150,000
SRY — locus Yp11.2; codes for production of the testes. It is also called “TDF,” short for Testis Determining Factor. SRY stands for “Sex-determining Region of Y-chromosome.” When mutated, Mullerian (female) production occurs instead, but the gonadal tissue does not develop as testes or ovaries and degenerates into streak gonads.
— Mutations of SRY are soley responsible for 10–15% of Swyer Sydrome cases, and an additional 10–15% of patients with other mutations causing Swyer Syndrome also have an SRY mutation. (It’s buried in this study, but searching ‘15%’ should pull it up.)
DHH — locus 12q13.2; codes for the production of desert hedgehog protein. It’s odd that such a protein would be called that, but it is named after the species of hedgehog scientists were researching on when they discovered the protein. It is involved with many areas of the body’s early development, the formation of the perineurium (protective membrane around each bundle of fibers in a nerve), and according to the last link above, “May function as a spermatocyte survival factor in the testes. Essential for testes development.”
— Without DHH function, testes (Wolffian structures) do not develop and Mullerian structures (the uterus and cervix) are able to develop in their place as Mullerian is the fetus’s default and only needs one X chromosome to make. However, without two X chromosomes, the fetus cannot make ovaries. The gonadal tissue degenerates into streak gonads.
MAP3K1 — locus 5q11.2; codes for the production of protein mitogen-activated protein kinase kinase kinase 1. MAP3K1 protein is the kingpin of regulating signalling pathways for a variety of body processes, including male sexual development processes. It binds to other molecules to activate and regulate them, including RHOA, MAP3K4, FRAT1, and AXIN1.
ARX — locus Xp21.3; codes for homeobox protein ARX, a transcription factor that regulates the expression of other genes including brain development and embryonic development. Mutations of it result in severe mental handicap among other serious disorders, found in the Pathology & Biotech section in the link to homeobox protein ARX.
— It is almost unheard of that mutations of ARX have resulted in Swyer Syndrome, but this study lists it as one if you search the gene’s name ‘ARX.’
— Swyer Syndrome caused by mutations of ARX would lead to extreme damage of brain structures and functioning.
ATRX — locus Xq21.1; codes for protein transcriptional regulator ARTX. It regulates the expression of other genes through chromatin remodeling. Among these are the genes HBA1 and HBA2, both necessary for the production of hemoglobin. It plays an important role in sex differentiation and mutations of it result in axing of the testicular development in trade for Mullerian defaulting, resulting in Swyer Syndrome.
— This is one of those very rare mutation locations for Swyer Syndrome as with ARX, and you can find it by searching ‘ATRX’ in the study linked in the above ARX passage about the mutation’s rarity.
CBX2 — locus 17q25.3; codes for chromobox protein homolog 2. It is a component of the polycomb group (PcG) multiprotein PRC1-like complex, mutations of which lead to cancers. It regulates and maintains the status of many other genes, and some of those genes are capable of suffocating anti-Mullerian activity leading to Mullerian development and Swyer Syndrome by CBX2 mutation.
— Because of this gene’s importance in the PcG PRC1-like complex group and mutations of which causing carcinogenesis, patients with Swyer Syndrome by mutations of CBX2 are at high risk for development and progression of cancer.
DMRT1 — locus 9p24.3; codes for doublesex- and mab-3-related transcription factor 1 and causes a form of Swyer Syndrome specific to its mutation. Quoted from the first link, “Transcription factor that plays a key role in male sex determination and differentiation by controlling testis development and male germ cell proliferation. Plays a central role in spermatogonia by inhibiting meiosis in undifferentiated spermatogonia and promoting mitosis, leading to spermatogonial development and allowing abundant and continuous production of sperm. Acts both as a transcription repressor and activator: prevents meiosis by restricting retinoic acid (RA)-dependent transcription and repressing STRA8 expression and promotes spermatogonial development by activating spermatogonial differentiation genes, such as SOHLH1. Also plays a key role in postnatal sex maintenance by maintaining testis determination and preventing feminization: represses transcription of female promoting genes such as FOXL2 and activates male-specific genes. May act as a tumor suppressor. May also play a minor role in oogenesis (By similarity).”
GATA4 — locus 8p21.3; codes for transcription factor GATA-4, which plays a key role in cardiovascular development and function. With regards to Swyer Syndrome, as quoted from the link, “Required during testicular development (PubMed:21220346).”
— Swyer Syndrome caused by mutations of GATA4 are at heavy predisposition to heart deformaties and dysfunction like artrial septal defect 2, ventricular septal defect 1, Tetralogy of Fallot, atrioventricular septal defect 4, and a “nonclassical” mixed gonadal dysgenesis if the gene retains some function rather than a nullifying mutations that would cause complete gonadal dysgenesis like Swyer Syndrome.
NR0B1 — locus Xp21.2; codes for nuclear receptor subfamily 0 group B member 1 (DAX1). It plays an important role in the development of the adrenals, hypothalamus, pituitary gland, and the development of the gonads. It is in charge of regulating the genes that are key in the development of these structures, so mutations of it axe the development of the gonads and in males causes Swyer Syndrome by NR0B1 mutation.
— Patients of this variant of Swyer Syndrome may also have congenital adrenal hypoplasia (note, not hyperplasia as in CAH, but undergrowth of the adrenals).
SOX9 — locus 17q24.3; codes for transcription factor SOX-9. It is a transcription regulator with a high control in development of the skeleton, chrondrocyte differentiation, and in utero sex development. Mutations that nullify this gene’s activity result in Swyer Syndrome via SOX9 mutation.
— Patients with this type of Swyer Syndrome may also have campomelic dysplasia.
WT1 — locus 11p13; codes for Wilms tumor protein. This protein is necessary for development of the gonads and kidneys. Obstruction of the gene can cause anti-Mullerian development to not occur and instead Swyer Syndrome will happen in males.
WWOX — locus 16q23.1-q23.2; codes for WW domain-containing oxidoreductase. Proper function of the gene suppresses the growth of tumors and induces apoptosis, but dysfunction of the gene due to mutation is associated with multiple types of cancers. While it is hard to find links tying mutations of this gene to cases of Swyer Syndrome, this study as linked far above contains it as a list of genes documented as causes if you search ‘WWOX.’
— Swyer Sydrome OMIM Entry (Here it is described as “46, XY true hermaprhoditism,” as in medicine hermaphroditism refers to an intersex disorder which causes complete reversal of the external sex phenotype and the opposite internal structures of gonadal sex [i.e., an XY patient with Mullerian structures, which is Swyer Syndrome]. It does not mean that there is a “hermaphrodite” in the sense of “both sexes” or “produces and uses both gametes.”)
— Intersex: Swyer Syndrome cannot occur in female (XX) individuals. It is a male-only disorder. Swyer Syndrome patients do not produce ova, and without the mutations causing their disorder (as with all XY “sex-reversals,” as they are termed for their switch in external sex phenotype), they would have developed full healthy Wolffian structures, been able to make and use sperm, and have a male external phenotype. Swyer Syndrome patients can only menstruate if an endocrinologist is overseeing HRT where estrogen is injected to complete puberty, allow for a period, and keep the bones and heart healthy. These menstruations are infertile; there are no ova produced at all. Simply it is to maintain uterine health by shedding buildup of lining as well as bone/heart maintenance.
— In-Depth View and Treatment (not specific to a sole gene’s mutation, includes tidbits on a few other disorders like ovotesticular disorder)
While there are a very high number of genes that when mutated result in Swyer Syndrome, it should be noted that all of them pertain to the production, transportation, activation, and use of anti-Mullerian hormone. Swyer Syndrome is a disorder of anti-Mullerian hormone pathway that causes Mullerian development in males. Different genes here also code for different important body functions (such as DHH and the perineunium that protects nerves) and may cause a myriad of health issues on top of Swyer Syndrome.
There is also a “nonclassical” Swyer Syndrome, called mixed or partial gonadal dysgenesis. As with complete gonadal dysgenesis, no ovaries are formed and no ova are produced or used, so this is still of the male sex. Mixed gonadal dysgenesis can be caused by mutations of any gene above, though by mutations that retain some functionality of the gene rather than nullifying mutations as in complete gonadal dysgenesis. “Swyer Syndrome” is the term only for complete gonadal dysgenesis and is not used for mixed gonadal dysgenesis.
(Also called pseudovaginal perineoscrotal hypospadias, when the patient begins developing male phenotype as puberty occurs.)
Rate of Occurence: no estimate
SRD5A2 — locus 2p23.1; codes for 3-oxo-5-alpha-steroid 4-dehydrogenase 2, responsible for the conversion of testosterone into the three times as androgenically potent steroid dihydrotestosterone (DHT).
— Endocrine Profile: normal to high testosterone levels, increased FSH and LH, low to no DHT
— Intersex: Only males are intersex. Female development is not affected by lack of DHT. In utero, DHT is solely responsible for external genitals’ formation and testosterone is not. This is why males with 5ARD present an external female phenotype at birth, sometimes with clitoromegaly sometimes with a normal-sized clitoris. Testes are still present, though may be internal, as anti-Mullerian hormone still has its ability to function. While presenting a female phenotype, of course these patients have no uterus or ovaries so they also lack a cervix and have a blind vagina. As puberty comes and drastically increases the male’s testosterone levels, the testes descend, penis grows, and male development finally takes place. Some patients with 5ARD will not produce enough testosterone for that development and may remain with a female phenotype. 5ARD patients in certain tribes are locally called “guevedoces,” but that is considered rude if you are outside of their culture. 5ARD males are just males with delayed sexual development. No 5ARD patient has periods, produces ova, or has Mullerian (female) structures.
— From an article on 5ARD patients:
5ARD males may be given HRT testosterone or Andractim DHT gel to help them develop more when they’re going through puberty or as adults, if they want.
Rate of Occurrence: 1 in 4,500
— “The cause of MRKH syndrome is unknown. Changes in several genes that are involved in development before birth have been identified in females with MRKH syndrome. However, each has been found in only a few affected individuals, and it is unclear whether these changes cause MRKH syndrome. Researchers are working to determine how genetic changes might lead to problems with reproductive system development in females.The reproductive abnormalities of MRKH syndrome are due to incomplete development of the Müllerian duct. This structure in the embryo develops into the uterus, fallopian tubes, cervix, and the upper part of the vagina. The cause of the abnormal development of the Müllerian duct in affected individuals is unknown. Originally, researchers suspected that MRKH syndrome was caused by environmental factors during pregnancy, such as medication or maternal illness. However, subsequent studies have not identified an association with any specific maternal drug use, illness, or other factor. Researchers now suggest that in combination, genetic and environmental factors contribute to the development of MRKH syndrome, although the specific factors are often unknown.It is also unclear why some affected individuals have abnormalities in parts of the body other than the reproductive system. Certain tissues and organs, such as the kidneys, develop from the same embryonic tissue as the Müllerian duct, and researchers suspect that problems during development could affect these organs as well.”
However, I would suspect that mutations of WNT4 are involved in at least some cases of MRKH as it is crucial for the development of both Mullerian stuctures and the kidneys, and a good number of MRKH patients have deformed or absent kidneys (referred to as renal dysplasia).
Lo and behold, from the UniProt page for WNT4 under Pathology & Biotech, there is listed a disorder of sex development called Mullerian aplasia that manifests the same as MRKH.
— “MRKH may be isolated (type I) but it is more frequently associated with renal, vertebral, and, to a lesser extent, auditory and cardiac defects (MRKH type II or MURCS association).”
— In-Depth View and Treatment (abstract available free but pay-for-full)
— Intersex: MRKH only affects females. The intersex symptom of MRKH is deformity or absence of the uterus, ovaries, vagina, and clitories. No males have MRKH as no males can have MRKH. Sometimes this variant with the absense of external structures is called “aphalia.”
Rate of Occurrence: 1 in 2,500 girls
— “This condition occurs in about 1 in 2,500 newborn girls worldwide, but it is much more common among pregnancies that do not survive to term (miscarriages and stillbirths).”
Genes Involved: Missing or incomplete second X chromosome, sometimes both X chromosomes but one is rendered completely dysfunctional by mutations; karyotype written as “45, X” or “45, X0.”
Health Concerns Associated with Turner Syndrome (Note: not all patients, but many will have these, some will not have any, and many will have some but not others)
— “About 30 percent of females with Turner Syndrome have extra folds of skin on the neck (webbed neck), a low hairline at the back of the neck, puffiness or swelling (lymphedema) of the hands and feet, skeletal abnormalities, or kidney problems. One third to one half of individuals with Turner Syndrome are born with a heart defect, such as a narrowing of the large artery leaving the heart (coarctation of the aorta) or abnormalities of the valve that connects the aorta with the heart (the aortic valve). Complications associated with these heart defects can be life-threatening.”
— Before Birth
— “Turner Syndrome may be suspected prenatally based on prenatal cell-free DNA screening ― a method to screen for certain chromosomal abnormalities in a developing baby using a blood sample from the mother ― or prenatal ultrasound. Prenatal ultrasound of a baby with Turner Syndrome may show:
— Large fluid collection on the back of the neck or other abnormal fluid collections (edema)
— Heart abnormalities
— Abnormal kidneys
— At Birth or During Infancy
— Wide or weblike neck
— Low-set ears
— Broad chest with widely spaced nipples
— High, narrow roof of the mouth (palate)
— Arms that turn outward at the elbows
— Fingernails and toenails that are narrow and turned upward
— Swelling of the hands and feet, especially at birth
— Slightly smaller than average height at birth
— Slowed growth
— Cardiac defects
— Low hairline at the back of the head
— Receding or small lower jaw
— Short fingers and toes
— In Childhood, Teens and Adulthood
— The most common signs in almost all girls, teenagers and young women with Turner Syndrome are short stature and ovarian insufficiency due to ovarian failure that may have occurred by birth or gradually during childhood, the teen years or young adulthood. Signs and symptoms of these include:
— Slowed growth
— No growth spurts at expected times in childhood
— Adult height significantly less than might be expected for a female member of the family
— Failure to begin sexual changes expected during puberty
— Sexual development that “stalls” during teenage years
— Early end to menstrual cycles not due to pregnancy
— For most women with Turner Syndrome, inability to conceive a child without fertility treatment.”
— Endocrine Profile: abnormally high FSH, LH, and gonadotropin
— Intersex: Only occurs in females. No male forms without the presence of Wolffian-determinant coding factors exclusive to the Y chromosome. There is no Y equivalent to Turner Sydrome; humans require at least one X to survive so all fetuses conceived with a singular Y karyotype do not live to be birthed. Turner patients commonly do not form ovaries and instead the tissue degenerates into streak gonads, but in some cases where partial functioning of a second X remains, ovaries may form. Almost all Turner Syndrome patients are infertile.
Some Turner patients may have almost complete functioning of their second X and look and have the same health level as anyone else.
Rate of Occurence: 1 in 500 to 1 in 1,000 boys
Genes Involved: An extra X chromosome has been placed into either the sperm or ova before conception, so the baby boy has an XXY karyotype.
Health Concerns Associated With Klinefelter Syndrome (again, not all patients, but a good number)
— “Other physical changes associated with Klinefelter Syndrome are usually subtle. Older children and adults with the condition tend to be somewhat taller than their peers. Other differences can include abnormal fusion of certain bones in the forearm (radioulnar synostosis), curved pinky fingers (fifth finger clinodactyly), and flat feet (pes planus).”
— “Children with Klinefelter Syndrome may have weak muscle tone (hypotonia) and problems with coordination that delay the development of motor skills, such as sitting, standing, and walking. Affected boys often have learning disabilities, problems with reading, and mild delays in speech and language development. Boys and men with Klinefelter syndrome tend to have better receptive language skills (the ability to understand speech) than expressive language skills (vocabulary and the production of speech) and may have difficulty communicating and expressing themselves. They tend to have anxiety, impaired social skills, a short attention span, and limited problem-solving skills (executive functioning).”
— “Compared with unaffected men, adults with Klinefelter Syndrome have an increased risk of developing type 2 diabetes, blood clots, involuntary trembling (tremors), breast cancer (if gynecomastia develops), thinning and weakening of the bones (osteoporosis), and autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis. (Autoimmune disorders are a large group of conditions that occur when the immune system attacks the body’s own tissues and organs.)”
— OMIM Entry (Couldn’t find one for just the syndrome itself; this one is the closest and focuses on its relation to testicular tumors. Information on this is primarly found in the “Molecular Genetics” section.)
— Intersex: Klinefelter Syndrome only occurs in males. The intersex symptom is inevitable onset of gynecomastia, lower sperm count, smaller penis and testes size, and low facial and body hair development. As they have proper-functioning Y chromosomes and anti-Mullerian activity, they produce all Wolffian structures, no Mullerian structures, and produce spermatozoa and not ova.
Rate of Occurence: between 1 in 17,000 and 1 in 50,000 boys
Genes Involved: Unintended inheritance of two extra X chromosomes from a dysfunctionally created gamete.
— “48,XXXY Syndrome is a chromosomal condition in boys and men that causes intellectual disability, developmental delays, physical differences, and an inability to father biological children (infertility). Its signs and symptoms vary among affected individuals.”
— “Most boys and men with 48,XXXY Syndrome have mild intellectual disability with learning difficulties. Speech and language development is particularly affected. Most affected boys and men can understand what other people say more easily than they themselves can speak. The problems with speech and communication can contribute to behavioral issues, including irritability and outbursts or temper tantrums. Boys and men with 48,XXXY Syndrome tend to have anxiety, a short attention span, and impaired social skills.”
— “48,XXXY Syndrome is also associated with weak muscle tone (hypotonia) and problems with coordination that delay the development of motor skills, such as sitting, standing, and walking. Affected boys and men tend to be taller than their peers, with an average adult height of over 6 feet.”
— “Other physical differences associated with 48,XXXY Syndrome include abnormal fusion of certain bones in the forearm (radioulnar synostosis), an unusually large range of joint movement (hyperextensibility), elbow abnormalities, curved pinky fingers (fifth finger clinodactyly), and flat feet (pes planus). Affected individuals may have distinctive facial features, including widely spaced eyes (ocular hypertelorism), outside corners of the eyes that point upward (upslanting palpebral fissures), and skin folds covering the inner corner of the eyes (epicanthal folds). However, some boys and men with 48,XXXY Syndrome do not have these differences in their facial features.”
— “48,XXXY Syndrome disrupts male sexual development. The penis is shorter than usual, and the testes may be undescended, which means they are abnormally located inside the pelvis or abdomen. The testes are small and do not produce enough testosterone, which is the hormone that directs male sexual development. The shortage of testosterone often leads to incomplete puberty. Starting in adolescence, affected boys and men may have sparse body hair, and some experience breast enlargement (gynecomastia). Their testes typically do not produce sperm, so most men with this condition are infertile.”
— (No OMIM Entry found)
— Intersex: Occurs in males only. The Y chromosome is there and functions, producing anti-Mullerian ability. Regardless of the number of X chromosomes, one “no” in the way of anti-Mullerian development from even a single Y causes male development. They still have Wolffian structures, the coding to produce spermatozoa, and a male phenotype, though they are infertile. The penis may be smaller and the testes may be undescended. They never have Mullerian structures, menstruate, or produce ova.
— Guys with XXXY Syndrome: (X)
Rate of Occurrence: between 1 in 18,000 and 1 in 40,000 boys
Genes Involved: Due to defects in the parents’ gamete production, inheritance of an extra X and an extra Y from a defective gamete.
— “48,XXYY Syndrome is a chromosomal condition that causes infertility, developmental and behavioral disorders, and other health problems in males.”
— “48,XXYY disrupts male sexual development. Adolescent and adult males with this condition typically have small testes that do not produce enough testosterone, which is the hormone that directs male sexual development. A shortage of testosterone during puberty can lead to reduced facial and body hair, poor muscle development, low energy levels, and an increased risk for breast enlargement (gynecomastia). Because their testes do not function normally, males with 48, XXYY Syndrome have an inability to father children (infertility).”
— “48,XXYY Syndrome can affect other parts of the body as well. Males with 48,XXYY Syndrome are often taller than other males their age with an average adult height of 6 feet 4 inches (193 cm). They tend to develop a tremor that typically starts in adolescence and increases with age. Dental problems are frequently seen with this condition; they include delayed appearance of the primary (baby) or secondary (adult) teeth, thin tooth enamel, crowded and/or misaligned teeth, and multiple cavities. As affected males get older, they may develop a narrowing of the blood vessels in the legs, called peripheral vascular disease. Peripheral vascular disease can cause skin ulcers to form. Affected males are also at risk for developing a type of clot called a deep vein thrombosis (DVT) that occurs in the deep veins of the legs. Additionally, males with 48,XXYY Syndrome may have flat feet (pes planus), elbow abnormalities, abnormal fusion of certain bones in the forearm (radioulnar synostosis), allergies, asthma, type 2 diabetes, seizures, and congenital heart defects.”
— “Most males with 48,XXYY Syndrome have an IQ that ranges from 70–80 with some degree of difficulty with speech and language development. Learning disabilities, especially those that are language-based, are very common in males with this disorder. Affected males seem to perform better at tasks focused on math, visual-spatial skills such as puzzles, and memorization of locations or directions. Some boys with 48,XXYY Syndrome have delayed development of motor skills such as sitting, standing, and walking that can lead to poor coordination. Affected males have higher than average rates of behavioral disorders, such as attention deficit hyperactivity disorder (ADHD); mood disorders, including anxiety and bipolar disorder; and autism spectrum disorder, which affects communication and social interaction.”
— (No OMIM Entry found)
— Intersex: Again, because of the presence of at least one non-mutated Y chromosome, only males have XXYY. No Mullerian structures, no ova production. Wolffian structures are present.
— Guys with XXYY Syndrome: (X)
That should just about cover it for sex chromosome aneuploidies. We can infer from all this information that they aren’t causing a third sex and instead cause many health concerns no matter the amount of chromosomes or combinations.
Rate of Occurence: extremely rare and unknown; actual human chimeras are incalculably rare
How this works: This is also called “tetragametic chimerism,” meaning that a baby has inherited genetics from four gametes instead of two. This occurs when a fraternal twin absorbs its twin zygote at some point in pregnancy, adding the twin’s DNA to different locations in its body, sometimes mixing the DNA sometimes not.
What sex then? If the gonadal tissue receives enough XX zygote DNA, the person will develop a female phenotype and sex development regardless of even being 96% XY DNA elsewhere. Sometimes, absorption of an opposite sex zygote’s DNA can cause development of ovotesticular disorder of sex development, which I’ll get into in its own section.
Here, the person was determined to be only one sex but then the opposite sex fraternal twin was absorbed. The person still only has the ability to produce and use one type of gamete, not both. It was not biology’s intention for the person to have both XX and XY cells and it does not represent nature’s desire to create a third sex. People are still phenotypically one sex or the other. You will not see a patient with a fully developed penis making ova. Most commonly the patient has mixed gonadal dysgenesis (described above in the Swyer Syndrome section).
Health Concerns Associated With XX / XY Mosaicism:
— Congenital Pulmonary Lymphangiectasis with Chylothorax (behind a paywall but the title alone tells you what’s going on)
— Perinatal Fatality (again, paywall, only abstract is shown)
— Medical Slide (See ‘45,X/46,XY’ and ‘46/XX’ and ‘46/XY’)
As with ovotesticular disorder, it is near impossible to find non-medical and positive photos of people with this disorder. I’d assume that sadly this is due to the shame caused by doctors only seeing them as a research photo op instead of a full patient and human being, not just because of the disorder’s rarity.
Please do not believe that XX / XY mosaics or Ovotesticular Disorder patients look any differently in the face than you and I. They are not “freaks.”
(60% of all patients with ovotestes are 46, XX. The remainder are XX / XY mosaic chimeras, for which refer to the above passage on XX / XY Mosaicism.)
Rate of Occurence: 1 in 83,000
Genes Involved: Most often in patients who are not mosaics, ovotesticular disorder is caused by faulty sperm genesis in which the father’s sperm production accidentally places one of his Y’s SRY regions onto the arm of another sperm’s X.
What sex? Patients with 46, XX ovotesticular disorder are all females who happened to receive male coding regions by accident and it is a “nonclassical” form of De La Chapelle Syndrome, which is described below. Most often the coding region is SRY, but it may also be caused by unnatural duplication or triplication of SOX9 or duplications or deletions in SOX3. (See sections ‘TEXT’ and ‘Genetic Heterogeneity of 46,XX Sex Reversal.’)
As for mosaics with ovotesticular disorder, see their info above.
There is not a condition of ovotesticular disorder where the patient has both a fully functioning penis and vagina, and so cannot make use of both gametes. The person still only has one reproductive capability (if not rendered infertile or physically unable), either pregnancy or impregnation. Persons with ovotesticular disorder do not add a new angle to human sexual reproduction and that is most important in realizing that they are not a third biological sex.
Health Concerns Associated With Ovotesticular Disorder:
— It is hard to find other information regarding health concerns as they would be specific to which genes are mutated, what hormone levels have been caused, and what quantity of each gonadal tissue has developed. Doctors also care less about these patients’ health and more about photographing their “freaky” patients for fame and fortune, so almost all case reports on ovotesticular disorder disregard the patient’s health in favor of talking about sexual development.
— Medical Slide (regards the karyotype, mutation pattern, and phenotype of patients)
— “True hermaphroditism [described as containing both varieties of gonadal tissue, though inability to use each to its fullest reproductive function] is very rare except in Southern Africa, where it is the most common intersex condition.”
Rate of Occurence: unknown
Genes Involved: In 80–80% of cases, unnatural translocation of SRY onto an arm of an X during father’s spermatogenesis. The other cases include mutations of SOX9, SOX3, RSPO1 and WNT4, all important genes in sex development.
— OMIM Entry (disregard ovotestis-related info here, as that only applies to “nonclassical” De La Chapelle Syndrome that manifests as ovotesticular disorder)
— Intersex: De La Chapelle Syndrome only occurs in females. It is intersex only because the patient is not actually male. While testes are present, they are very small and unable to produce sperm. The person does not produce ova either. Because this is a female disorder, some breast development may take place and there is lower-than-average testosterone production. The patient may be given testosterone HRT to help with prevention of gynecomastia and influence secondary sex development, if wished.
And with that we have covered all intersex disorders that I have been able to find.
Do intersex people categorize a third sex or disprove that human sex is only male or female? No.
Nothing listed above shows any option toward reproduction other than pregnancy or impregnation, sperm or ova, Mullerian or Wolffian. There is no intersex variant that can make and successfully use both ova and sperm. There is no intersex variant with strict Mullerian development that makes sperm, and no intersex variant with strict Wolffian development that makes ova.
Also, we can tell that different types of being intersex are exclusively tied to mutations of certain genes, which are mutations leading to health concerns or sometimes death. If intersex were a third sex, different disorders wouldn’t be tied to desctruction of function in very specified genes and would instead be healthfully inherited development through a third sex chromosome.
Intersex disorders also tend to be specifically common in some ethnicities and not others, such as virilizing CAH in Ashkenazi Jews, lipoid CAH in Koreans, and 5ARD in the Dominican Republic, some highland tribes in New Guinea, Lebanon, and Turkey. All around the world, no matter where you go, almost 50% of people are male and 50% of people are female (save for countries with high rates of femicide). If intersex people were a third sex, we would have each condition show equal rate of occurrence in all ethnicities across the board. But we do not.
We also would not be able to mix “sexes” like having both Klinefelter Syndrome (XXY) and CAH.
Biological sex in humans is dichotomous. We can only be male or female, but there is a spectrum of how males present and a spectrum of how females present. Intersex people do not disprove the existence of biological sex or prove the existence of new sexes; we merely have mutations of genes that altered our course of development, though none that truly reverse our sex and allow us to fully perform the reproductive ability of the opposite sex or both sexes at the same time. Many of us are sterile and unhealthy, and many of us have to live on pharmaceuticals to care for the poor bone and heart health that is so frequent among intersex disorders.
Everyone, please stop spreading misinformation about our bodies as political pawns. We’re just here, a little bit different, but we’re still like you, not some third other. The world needs to stop caring so much about what those of us who are intersex look like, and start caring more about our health and comfort in our own bodies.
Published on Medium on December 31st, 2018.
Always feel free to contact me for more information. I am here to provide intersex information for those who seek it.