Differential Diagnosis

Besides AIS, there are a number of related intersex variations characterized by XY chromosomes and testes, but which have other causes than the body being unresponsive to androgens such as testosterone. These variations have been described by the generic term "male pseudohermaphroditism". While this term is unpleasant for some, it is the only widely used and understood term that fits all these variations.

These variations all have in common the fact that a fetus begins with XY chromosomes and is on the pathway to developing as a male, but that something happens which diverts its development in the female direction. Specifically in AIS, 'mutations' in the AR gene prevent androgen receptors from working properly, which makes cells less responsive to androgens or prevents cells from using these hormones at all.

The support group is committed to providing help and support to those with other variations related to AIS. We do not feel that the precise details of someone's metabolic defect or the cause of their condition are as important as the effects, and in most of these cases, the effects are very similar to those of AIS.

A sizable proportion of those who have contacted the support group who believe they have AIS, or who been told they have AIS by physicians, subsequently turn out to have a related but distinct condition. This happens especially often in the case of those with a PAIS diagnosis.

Misdiagnosis can be the result of a plain error on the physician's part. Since AIS is a rare condition, few physicians have enough breath of experience with the condition to recognized a patient who does not fit the typical pattern. Complete AIS affects 2 to 5 per 100,000 people who are genetically male. Partial androgen insensitivity is thought to be at least as common as complete androgen insensitivity.

Yet AIS is the most widely known among MPH-isms, and is likely to be the first diagnosis considered. AIS is also well known and noted in the medical literature as a condition where the XY chromosomes and testes contrast with the patient's feminine personality traits and identification with the female role. This may lead some physicians to consider an AIS diagnosis less stigmatizing than some of the alternatives. Therefore, they may feel reluctant to consider alternative diagnoses.

There are several reasons why it is better for a patient to have a complete and accurate diagnosis. Since related variations are inherited in different ways from AIS, correct diagnostic information may be of interest to other family members. About two-thirds of all cases of androgen insensitivity syndrome are inherited from mothers who carry an altered copy of the AR gene on one of their two X chromosomes. The remaining cases result from a new mutation that can occur in the mother's egg cell before the child is conceived or during early fetal development.

An accurate diagnosis can also have an impact on treatment decisions. A very important consideration is that, in nearly every other condition besides AIS itself, the body is fully responsive to testosterone. Therefore, testosterone, either from the body itself in a spontaneous puberty, or from hormone replacement, can cause male characteristics - "virilisation" - to develop. For someone who identifies as a girl, this could be disastrous. In grades 3 or higher PAIS, this virilisation either does not happen, or is very weak. However, if the diagnosis is known to be of another condition than AIS, prepubertal gonadectomy and avoidance of testosterone in HRT is indicated.

Determining an accurate diagnosis depends on careful assessment of all clinical features. In someone with a history of having had high blood testosterone levels for a significant length of time without undergoing substantial virilisation, this is strong evidence of reduced action of the androgen receptor, and indicates a diagnosis of AIS. However, it is more useful to have inaccurate diagnosis before the age of puberty.

The Sex hormone binding glubulin suppression test using the anabolic steroid Stanazolol may be useful in confirming a PAIS diagnosis, and can be done in the neonatal period (see references below). Tests involving administration of gonadotrophic hormones are useful in determining whether the body is able to produce testosterone, or whether the problem actually involves ability to use testosterone.

A. Failure of development of testes in an XY person

Development of testes depends on a number of genes. One of these genes is on the Y chromosome, another is on the X chromosome, and several more are on various autosomes (non-sex chromosomes). If any of these genes is missing or non-functioning, then the fetus will develop streak gonads instead of testes. The streak gonads lack both germ cells and hormone-producing cells. They consist only of the fibrous tissue that normally supports the ovaries. This condition is known as Swyer syndrome. Except for the lack of ovaries person with Swyer syndrome will have normal female anatomy, including a uterus, but will not go through the changes of puberty without hormone replacement. With hormone replacement, she will experience both menstruation and breast development.

A small minority of patients with Swyer syndrome do experience some breast development and menstruation at the age of puberty, however, this usually lasts for only a short time. This happens because the streak gonads sometimes begin to develop as ovaries. This is especially likely to happen in the form of Swyer syndrome caused by a gene defect on the X chromosome. However, in the absence of a second X chromosome, this ovarian tissue degenerates very rapidly, leading to the what is normally called "menopause" ,within a short time. The patient will still ultimately require hormone replacement.

Turner syndrome is a condition caused by a person having a single X chromosome and no Y chromosome. Anatomically, Turner syndrome patients are similar to those with Swyer syndrome, except that they often have short stature and some other features characteristic of Turner syndrome ("stigmata"). Turner syndrome is very distinct from AIS, and is unlikely to mistaken for AIS. However, there are also patients who have a mixture of 45,X and 46 XY cells in their bodies. This condition, called 45,X/46, XY mosaicism, or "mixed gonadal dysgenesis", has the potential to be mistaken for PAIS. As in PAIS, the external anatomy can be anywhere within a wide range from typically male to typically female. In some cases, a testis develops on one side of the body, and a streak gonad on the other, with a partial uterus on the side with the streak gonad.

It can also happen that testes develop initially in an XY fetus, then degenerate at some time during fetal life. When this happens in very late fetal life, the result is an anatomically normal male with missing testes. If it happens so early in fetal life that the testes never exert any effect at all on development, the result is indistinguishable from Swyer syndrome.

Since regression of the mullerian ducts happens at an earlier gestational age than differentiation of the external genitalia, inhibition of uterine development will tend to be more complete than masculinisation of the external genitalia, which is similar to what is observed in PAIS, although the cause is different.

Regression of the testes at a still later stage, after the structure of the genitalia has differentiated as unambiguously male, but before the phallus has completed its growth leads to "micro phallus" - a condition where the genitalia are unambiguously male in structure, but the penis is abnormally small.

B. Problems with the body's ability to produce testosterone.

There are a number of variations characterised by failure of the body of an XY person with testes to produce testosterone. One cause can be insensitivity of the body to luteinizing hormone, which is produced by the pituitary gland and which stimulates the Leydig cells in the testes to develop and produce testosterone. This is called either Leydig cell hypoplasia or luteinising hormone insensitivity. (These are the two main manifestations of this one condition.) In Leydig cell hypoplasia, the external genitalia are normally female, or only slightly ambiguous. As in AIS, MIF prevents development of the uterus. At puberty, there will be no feminisation or masculinisation, except for possible development of a small amount of body hair.

Testosterone synthesis can also be interfered with by failure of a number of enzymes needed for testosterone synthesis. There are a number of enzymes involved. In some cases, spontaneous puberty may consist of both weak virilisation and weak feminisation, while in the case of deficiency of other enzymes, virilisation will predominate. The genitalia are usually mildly ambiguous.

Deficiency of the 5-alpha 2 reductase enzyme prevents testosterone from being converted to Dihydrotestosterone, a related hormone which is essential for complete prenatal masculinisation. Dihydrotestosterone binds to the same receptor as testosterone, only more strongly. Its effect at puberty is only mildly stronger than that of testosterone.

Individuals with 5-alpha reductase deficiency are born with partly masculinized female genitalia, but the natural course of puberty in 5-alpha reductase deficiency is not feminizing, but masculinizing. In some countries where modern medical care is not available, there is no remedy for the pubertal masculinization that occurs to these individuals at puberty. In some cases, this has resulted in a change in their gender role from female to male.


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