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Related Conditios – AIS (Androgen Insensitivity Syndrome)

Introduction

A lot of the web page is devoted to varied XY feminine intersex circumstances aside from AIS (AIS having been described in detail elsewhere on the location) and includes a temporary point out of the dreaded ‘male-pseudohermaphrodite’ umbrella term!

However firstly we contemplate some XXX feminine non-intersex circumstances which share widespread features with some XY feminine intersex circumstances, akin to lack of vaginal improvement. It then seems to be briefly at true hermaphroditism. The page doesn’t cover XX feminine intersex circumstances comparable to Congenital Adrenal Hyperplasia (CAH). For info on any such condition please seek advice from the web pages of the CAH help teams.

‘XX Female’ Circumstances

These will only be thought-about briefly because the major focus of this website is on ‘XY female’ circumstances. Nevertheless, they do have some features, corresponding to vaginal hypoplasia (underdevelopment), in widespread with some XY female circumstances and we now have members of our group who have MRKH. See Overview for a summary of normal feminine improvement.

For assets associated to XX circumstances resembling MRKH please seek advice from our (PDF format) Vaginal Hypoplasia Info Sheet. See additionally Patricia DeFrain’s Index to Articles, Books and so forth. on MRKH Syndrome (and Related Issues), an inventory of publications from Patricia’s (now defunct) website. See also Links to Other Sites.

Observe: It’s worthwhile to have a PDF Reader on your PC so as to entry PDF information. See About this Website page for more information.

Mayer Rokitansky Kuster Hauser (MRKH) Syndrome

Absent or incomplete vagina, incompletely developed uterus with regular Fallopian tubes and ovaries. Normal breast improvement and pubic hair. Failure to menstruate.

Mullerian (Duct) Aplasia or Mullerian (Duct) Failure

Absence of the higher vagina, cervix and uterus, with incomplete or absent Fallopian tubes however regular ovarian perform. Normal external genitalia, breast improvement and pubic hair. Lack of menstruation. Actual trigger not recognized (an autosomal X-linked inheritance from the daddy, an autosomal recessive genetic trait and spontaneous mutation have all been postulated). Typically accompanied by abnormalities of the urinary tract (e.g. lacking or mis-located kidney) and/or skeletal (primarily spinal) abnormalities.

Confusion exists in the medical group in regards to the difference between MRKH and Mullerian Aplasia. Some researchers feel that the presence of a rudimentary uterus and normal Fallopian tubes differentiates MRKH Syndrome from Mullerian Aplasia. Nevertheless, others feel that they could primarily be the identical dysfunction.

Vaginal Atresia

Absence of the decrease portion of the vagina (replaced with 2-Three cms of fibrous tissue) but with regular higher portion. The cervix, uterus, Fallopian tubes and exterior genitalia are all normal. Normal breast improvement and pubic hair. Failure to menstruate. In the medical literature, Mullerian Aplasia and Vaginal Atresia are typically grouped together beneath the term ‘Congenital Absence of the Vagina’.

MURCS Affiliation

A really rare condition characterized by several ‘associated’ developmental abnormalities present at start. MURCS stands for M(ullerian) R(enal) C(ervico-thoracic S(omite) abnormalities. Affected people are females with Mullerian Aplasia, renal abnormalities together with absent or mis-located kidney(s), and abnormalities of the spinal twine, ribs and/or arms on account of improper improvement (dysplasia) of part of the embryo (cervico-thoracic somite).

True Hermaphroditism

An individual who has each testicular and ovarian tissue is claimed, in previous terminology, to be a true hermaphrodite. Hermes was the God of Intelligence and Wisdom, and Aphrodite was the Goddess of Beauty and Love. A real hermaphrodite might have a separate ovary and testis but more generally has anovo-testis which is a gonad containing both types of tissue. This may be on one or each side of the physique. 60% of true hermaphrodites could have an XX karyotype and the remainder might have an XY karyotype or a mosaic (a mix). The external genitalia could also be ambiguous or female. There could also be a uterus or (more commonly) a hemi-uterus (half uterus) on the aspect the place there’s ovarian tissue. The individual could also be raised female or male, and sometimes undergoes genital surgery. The ovo-testis is often removed because of the danger of malignancy.

‘XY Female’ Circumstances

This rest of this web page concentrates on XY circumstances which are just like AIS.

Biologically speaking, the pathway in the direction of a female type seems to be the default for humans, whereas the path for improvement of a male foetus is extra tortuous, and depending on many various genes, every of which might be defective. This means that there is a set of a fairly assorted circumstances during which a foetus with XY chromosomes develops as a baby woman.

Amongst these are:

  1. Failure of formation of testes resulting from quite a lot of causes (i.e. Swyer syndrome or pure XY gonadal dysgenesis, XO/XY mosaicism, testicular regression syndrome and so on.).
  2. Underdevelopment of cells in testes on account of unresponsiveness to hormones from the pituitary gland (i.e. Leydig cell agenesis or hypoplasia).
  3. Enzymatic defects in testosterone biosynthesis (i.e. deficiencies of enzymes 5-alpha reductase, 17-ketosteroid reductase, 17-alpha hydroxylase, Three-beta hydroxysteroid dehydrogenase, 17-beta hydroxysteroid dehydrogenase and so on.).
  4. Insensitivity of genital tissues to androgens (i.e. AIS).

In No. 1 the testes themselves fail to type correctly. Nos. 2 and 3 come beneath the broad heading of a failure of androgen (male hormone) manufacturing by the testes. No. four, AIS, is the most typical, and subsequently one of the best recognized of those circumstances and is described on different pages of this website; so we’ll focus right here on the other three kinds of condition. But first, we’ve to mention a much hated medical umbrella term and then say a bit about geting an correct analysis.

‘Umbrella’ Time period (MPH)

These numerous ‘XY female’ circumstances have been grouped by docs underneath an umbrella term referred to as “male pseudo-hermaphroditism” (MPH). The male a part of the time period refers back to the medical notion that the primary determinant of the maleness is the presence of testes, and hermaphroditism refers to the obvious inconsistency of this notion within the face of an outwardly female patient. The pseudo- in the identify acknowledges the fact that these sufferers usually are not actually hermaphrodites, since they don’t often have each female and male gonads.

This time period, which is a hangover from a time earlier than trendy genetic testing turned obtainable, is hated by most sufferers (see Terminology Debate). Nevertheless, we point out this time period here because there isn’t a different generally used term that covers all these circumstances; and lots of affected individuals and households come to us quoting this term as their analysis. It might be a welcome move if docs, researchers and affected person groups might work together find a better term to substitute for MPH. The terms ‘XY female’ or ‘XY woman’ find favour with most of our group members, though we concede that this doesn’t cowl the entire range as a result of it excludes those that might determine as intersexed when it comes to their gender.

Lately (2006) a brand new terminology has been proposed. See Terminology Issues on the What’s AIS? page.

Notice: Defects in synthesis, secretion or response to Mullerian Duct Inhibitory Issue or MIF (also referred to as Anti Mullerian Hormone, AMH) end in feminine genital ducts in men; while these circumstances fall beneath the broad medical term of MPH, they’re basically totally different in that the affected people are in any other case regular males, i.e. there’s a match between phenotype and genotype. Environmental chemical compounds also can cause some XY foetuses to develop as women, however such circumstances will not be described here, as we consider genetic causes.

Overlap with AIS

The AIS Help Group offers info and help to those with AIS and intently related circumstances. It has ‘AIS’ in its identify merely as a result of the founder member was the mother of a kid with AIS and we’ve got by no means modified the identify. We feel that a similarity of consequence, when it comes to bodily options and gender id, is more essential than the precise nature of someone’s condition at a mobile degree. And in a lot of the circumstances listed above, the consequences are similar to these of AIS.

A family info officer wrote from a hospital abroad, requesting info on behalf of a family, as follows:

I have a family with a toddler who has been recognized as having Swyer syndrome. They have asked me to make contact with you to see should you can provide them with details about this syndrome. They’re eager to have any info obtainable. Of specific interest is the experience of different families – the child is simply 4 months previous. The infant’s gonads have been removed and they’re keen to seek out out about what to expect at puberty. Is it attainable that you’ve one other household in your books in _____ [country].

We replied:

Sadly we are solely in touch with one household in ______ [country] they usually have a teenage AIS daughter. But it’s virtually irrelevant which specific condition a teenager has (AIS, Swyers, 5 alpha-reductase deficiency and so forth.) when it comes to getting helpful help as a result of it is the psycho-social ramifications which are so probably large, and these are typically universally applicable across these circumstances. So much in order that while mother and father and docs might focus their consideration on the medical/physical/developmental features, these could be of secondary importance in the eyes of the young ladies affected compared to whether or not or not the adults around them appear to simply accept their condition, and to encourage truthful, open and full dialogue, and get in touch with with other affected kids.

So our recommendation to the household can be to ask their marketing consultant what to anticipate at puberty but to not concentrate on this too much at this stage and to use the years until then to teach themselves absolutely relating to the psycho-social features. And to do that, it doesn’t really matter whether they are learning concerning the experiences of Swyers, or AIS, or….no matter…. as a result of the same rules apply. And aside from attending group conferences, one of the simplest ways for folks to understand the range of issues that kids with these circumstances can expertise as they grow up is to learn the accounts in our publication.

Mis-Analysis

Fairly a big proportion of those who contact the group with a analysis of  “Partial AIS (PAIS)” end up, on subsequent investigation, to have a related however distinct condition. All these circumstances, including AIS, are rare and few docs may have come across enough patients to allow them to fine-tune the analysis, particularly since AIS is probably the most extensively recognized of them and is subsequently the probably analysis to be thought-about first.

AIS is described relatively regularly in the medical literature as a situation through which the patient’s XY chromosomes and testes contrast together with her female appearance and gender id, while there’s much less literature describing the opposite circumstances in these phrases, as they’re extra uncommon. Perhaps this leads some physicians to think about AIS as a more acceptable, and perhaps less stigmatising analysis than a number of the options?

Dr. Cathy Minto (see Really helpful Clinicians) introduced a paper at a current (2000) congress and reported that of 47 ‘XY female’ patients seen on the University School Hospitals, 47% had an correct analysis, 32% are thought-about inaccurate, 15% have been changed and 6% have unknown aetiology as a result of pre-gonadectomy outcomes are unavailable.

Importance of Right Analysis

One of many many unfortunate elements of a) secrecy and denial, and b) mis-diagnosis, in these circumstances is the effect on different relations. The varied circumstances might have totally different modes of genetic transmission; and aside from the disastrous effects on the affected person of paternalism and lack of expertise, other relations may nicely have a legitimate interest in whether or not the situation might manifest in their youngsters. In order that they need correct info too. This can’t occur if the whole thing is shrouded in taboo and/or ignorance.

An correct analysis can also be essential in governing remedy selections. For example, in non-AIS circumstances the physique might be absolutely conscious of androgens and this may increasingly end in virilisation at puberty. In PAIS Grade 3 or greater, this virilisation either does not happen or could be very weak, however in somebody with one of many other circumstances, and who identifies as a woman, this might happen and be very unwelcome. Within the latter case, pre-pubertal gonadectomy (and avoidance of testosterone-based hormone remedy) can be indicated.

Reaching an accurate analysis depends upon a careful assessment of all medical and biochemical options. Exams will probably be carried out to determine whether or not there is perhaps a problem in producing androgens or with the physique’s capacity to use them in masculinising the physique.

We’ll now contemplate the varied ‘MPH conditions’ in more detail.

1. Failure of Testes Formation

This is also called “dysgenic pseudo-hermaphroditism” and may be regarded as a failure of the development of testes in the presence of XY chromosomes. Improvement of testes is determined by a variety of genes (one on the Y chromosome, one other on the X chromosome, and a number of other extra on numerous autosomes or non-sex chromosomes).

Swyer Syndrome

Swyer syndrome, or “pure XY gonadal dysgenesis”, is the identify given to a condition by which individuals possess a 46 XY karyotype and feminine external genitalia. Ladies with Swyer syndrome haven’t any ovaries or testes, but have “streak” gonads that lack both germ cells and hormone-producing cells; they only include fibrous tissue. It is thought that the gonads might begin to develop in the foetus however then deteriorate, abandoning the streaks. Or, it could possibly be that a mutation inhibits the perform of a portion of the Y chromosome, the portion that may trigger the sexual organ tissue of the embryo to become testes.

Swyer people have a traditional vagina and uterus (the so-called Mullerian buildings). Nevertheless, with neither ovaries nor testes there are usually not sufficient hormones to advertise pubertal sexual improvement, and often there isn’t a breast enlargement or pubic and underarm hair. Swyer syndrome is usually recognized when young adults are evaluated for delayed puberty, as menstruation does not occur naturally. Some people have a minimally enlarged clitoris. Hormone alternative causes improve in breast measurement and underarm and public hair, and menstruation is possible if the right hormone regime is adopted. In some instances, streak gonads develop tumours which produce hormones, thereby leading to modest breast and public hair improvement and minor menstrual recognizing. Removing of the streak gonads is carried out to attenuate the danger of cancerous growths.

Individuals with Swyer syndrome have reported utilizing quite a lot of hormone alternative therapies that embrace estrogen, and progesterone. Some have found adding low levels of testosterone to be helpful. Swyer individuals will not be androgen-insensitive and subsequently do reply to androgens corresponding to testosterone. This remedy is initiated on the time of puberty.

Since Swyer syndrome ladies posses a uterus they will get pregnant, via implantation of a fertilized donated egg in an in vitro fertilisation process. As they lack ovaries, they don’t ovulate.

Swyer syndrome might end result from a deletion along the Y chromosome, or a mutation in the SRY, the sex determining region on the Y chromosome, or from a mutation in one other gene that impacts the perform of the sex determining area genes on the Y chromosome. There’s some evidence to recommend that Swyer syndrome is inherited, although it might even be the result of a brand new mutation. Swyer syndrome is estimated to happen in lower than one % of the population.

(The above part is predicated on text kindly provided by a gaggle member with Swyer syndrome.)

One among our medical advisers answered an enquiry from a gaggle member with Swyer syndrome who was involved as as to if she had an obligation to tell her nieces of her condition (she most popular to keep it personal if at all attainable). Her neices would not have the situation but she was frightened in case they is perhaps carriers. He replied as follows:

It is extremely uncommon for Swyer’s syndrome to be inherited and to my information, the familial type only occurs as sister pairs and does not move vertically by way of a family. I might be pretty categorical subsequently that your nieces won’t be affected [as carriers] and that there isn’t a purpose why they should be told of your situation.

We sought additional info on her behalf from another of our advisers, an skilled in genetics of intersex circumstances, who replied:

Swyer syndrome is the eponym for what we classically regard as full XY gonadal dysgenesis. In that state of affairs, inactivating mutations within the SRY gene could also be discovered, but solely in 15-20% of individuals [with the syndrome]. Whether service detection is feasible all depends upon whether there is a mutation which might be recognized in yourself. You would wish to see a genetic counsellor to begin with and that might be organized by your common practioner. Various laboratories can display for mutations in the SRY gene, including our own.

We do not know what is the cause in the giant the rest; work is ongoing taking a look at SF1, because the occasional patient has been discovered with a mutation on this gene. In our collection we have now not found a mutation in SF1.

SRY is on the Y chromosome and so can only be passed from father to son [XY child]. So nieces who are undoubtedly recognized to be XX or undoubtedly wouldn’t have gonadal dysgenesis clinically (for example have menses or are fertile) can’t either have the mutant gene or be carriers. What is puzzling about SRY mutations, nevertheless, is finding the same mutation in the ‘normal’ father of the affected Swyer subject or within the brother of the subject (as we now have discovered just lately). We have no idea why these normal males didn’t develop Swyer, but things like incomplete genetic penetrance or somatic mosaicism have been invoked but with out proof.

Simply to add one other degree of complexity, XY gonadal dysgenesis can be inherited as an X-linked disorder [the mechanism that applies in AIS] and a few proof [exists] from family studies of maybe autosomal inheritance (see Williams Textbook of Endocrinology, 10th Version). Even less is understood concerning the genes in these varieties.

I end by emphasising once more that genetic counselling is clearly more simple when the precise genetic abnormality is understood. Even when an SRY mutation is discovered, it is probably not that straightforward to counsel, as defined above. The most effective stopping off point if an individual needs recommendation on these issues is to ask to see a medical geneticist.

XO/XY Mosaicism

Turner syndrome is a situation by which an individual has a single X sex chromosome and no Y chromosome. Anatomically, Turner syndrome sufferers are just like these with Swyer syndrome, with a serious physical distinction being in peak: Turner people are often underneath five ft tall, while Swyer people are of regular stature.

Turner syndrome could be very distinct from AIS, and is unlikely to mistaken for AIS. Nevertheless, there are patients who have a mix of 45,X and 46,XY cells of their our bodies, leading to a situation generally known as 45,X/46,XY mosaicism, or “mixed gonadal dysgenesis”, which has the potential to be mistaken for PAIS. As in PAIS, the exterior anatomy could be anyplace inside a variety from sometimes male to sometimes feminine. In some instances, a testis develops on one aspect of the body, and a streak gonad on the other, with a partial uterus on the aspect with the streak gonad.

Testicular Regression Syndrome

The testes disappear at a really early gestational age. The term Vanishing Testis Syndrome is usually used for the type of this the place the regression occurs late in foetal life, and the genitalia are shaped as usually male.

Some instances recognized as Swyer syndrome may very well be instances of testicular regression the place the testes disappear at a particularly early gestational age. This might be so in instances of ‘Swyer syndrome’ with solely a partly developed uterus, which strongly means that there was testicular tissue around in early fetal life, but alternatively this may occur before MIF could be produced, so the testes would vanish “without leaving a trace”.

2. Underneath-development of Leydig Cells

Leydig Cell Hypoplasia

Beneath normal circumstances the foetal testes accomplish two things: they produce Mullerian Inhibitory Issue (MIF) they usually produce testosterone. In some instances, the cells that produce MIF (referred to as Sertoli cells) work normally, whereas the cells that produce testosterone (referred to as Leydig cells) don’t develop properly. This situation is called Leydig Cell Hypoplasia (hypoplasia means underdevelopment) and the person develops underneath less or in some instances no testosterone, and consequently has a corresponding degree of feminization. As a result of the Sertoli cells are regular, and MIF is produced normally, they don’t have improvement of uterus or Fallopian tubes.

There could also be a number of causes for underdevelopment of Leydig cells, but it’s typically a consequence of a defect of the receptor for the Luteinizing Hormone (a pituitary hormone), and in these instances the condition can also be referred to as LH Resistance. The LH receptor is used for activation of Human Chorionic Gonadotropin (hCG), in other phrases, the hormone that comes from the placenta (chorionic) that’s chargeable for improvement of gonads (gonadotropin).

In distinction with AIS, the androgen receptor is sort of useful. Androgens will subsequently cause virilization, in each delicate and extreme instances of LHR. XY ladies with severe levels of LHR won’t produce any androgens at pubertal age so, in contrast to in AIS, the conversion of androgens to oestrogens (a course of referred to as ‘aromatization’) doesn’t happen as a way of effecting a pure feminizing puberty. They respond properly to estrogens, nevertheless, and may develop pubic and underarm hair just like unaffected ladies (as a result of additionally they reply to androgens, in contrast to CAIS ladies).

It is value noting that in contrast to AIS, LCH includes a defect on an autosome (not on a intercourse chromosome) and requires two mutated genes, one from the daddy and one from the mother. This has a number of repercussions. In contrast to AIS, it’s attainable for XX ladies (who may need siblings with LCH) to also have LH Resistance. This leads to infertility, but with improvement of uterus, ovaries, and so on. It’s also value remembering that fertile brothers as well as sisters could also be carriers. As a result of it is often crucial for both mother and father to be carriers for someone to have LH Resistance, the situation is more probably when there’s widespread ancestry between the mother and father.

Three. Enzymatic Defects in Testosterone Biosynthesis

There are several enzymes which might be a part of the standard strategy of testosterone synthesis.

Some enzymes (e.g. 17-ketosteroid reductase, 17-alpha-hydroxylase, Three-beta-hydroxysteroid dehydrogenase, 17-beta-hydroxysteroid dehydrogenase and so on.) facilitate the production of testosterone; and others (e.g. 5-alpha reductase) facilitate the conversion of testosterone to a stronger type that’s needed for full improvement of male genitalia.

So if any of these enzymes usually are not produced, then foetal masculinization does not happen and as an alternative the child develops as a woman with inner testes. In some instances, the enzymes work partially, and in these instances there is a variable diploma of masculinization or feminization. The circumstances also range in accordance with what occurs at puberty, i.e. virilization, feminization, or ‘nothing’ (‘eunuchization’, in the event you like stigmatizing language).

Some of these enzymes, comparable to 17-ketosteroid reductase, 17-alpha-hydroxylase, 3-beta-hydroxysteroid dehydrogenase, 17-beta-hydroxysteroid dehydrogenase and so forth, are necessary for the development of both feminine and male reproductive organs, and can also be necessary for the event of the adrenal gland.

5-alpha-reductase Deficiency

5-alpha-reductase is an enzyme that converts the weaker testosterone into the more potent dihydrotestosterone (DHT). When this enzyme is deficient (a situation referred to as 5-alpha-reductase deficiency) the infant develops as a woman. Nevertheless, at puberty testosterone manufacturing often will increase and is enough to trigger virilization, so in such instances (where the kid identifies strongly with a female position) it’s advisable to carry out a gonadectomy earlier than puberty. However, there are instances the place the kid naturally migrates to a male position. Subsequently, a conservative strategy that comes with listening to the child is crucial. 5-alpha reductase deficiency, in contrast to AIS, includes a defect on an autosome (not on a sex chromosome) and requires two mutated genes, one from the daddy and one from the mom.