Wednesday, September 30, 2009

Approach to the Infant with Ambiguous Genitalia

We all have subjects that are difficult to learn. And since difficulty sometimes breeds resentment, some of us tend to spend a little less time reading subjects we don't like. This propagates the difficulty.

For me, the whole issue of ambiguous genitalia was difficult to understand. Until now ...

Let's start by realizing a few basic priniciples. All fetuses, whether genetically male or female, will progress towards the path of being a female unless something tells them not to. In a genetically male fetus, at around week 9 of gestation, a gene on the Y-chromosome called the sex-determining region Y, SRY,  produces a protein called the SRY protein, also known as the testes determining factor. (It's almost as if the cosmic forces were saying "SORRY, you're going to be a male"). This SRY protein initiates the formation of testes. The newly formed testes being to release two hormones - a mullerian duct-inhibiting substance that causes regression of the derivatives of the mullerian duct (oviducts, uterus, inner one-third of vagina), and testosterone which basically stimulates the formation of the external genitalia.

Without the cosmic apology that is SRY, the primitive gonad develops into an ovary. Without testes producing mullerian duct-inhibiting substance, the oviducts, uterus, and inner one-third of vagina continue to form. In the absence of testosterone, the female external genitalia will continue to develop. Can you imagine what would happen if the pregnant mother is taking exogenous androgens during this critical period of development? (Answer)

So, this explains how the Y-chromosome predicts phenotypic sex. But as usual, mutations can screw up things. A mutated SRY gene may not produce SRY protein, and the XY baby will become a phenotypic female (Swyer syndrome). Alternatively, a SRY gene may be translocated from a Y-chromosome to an X-chromosome during sperm formation in the father. An X-chromosome will thus contain an SRY gene. The resulting fetus, genotypically XX, will develop into a male (XX male syndrome).

Ok, so now we know what makes a male a male, and why females are superior.

So, when a baby is born and you cannot quickly answer the parents' question regarding it's sex, you need to have a clear understanding of the pathophysiology of sexual determination to guide your workup. Your first step is to answer a fundamental question - is the baby a female that has been virilized (androgen excess) or is it a genetic male with underdevelopment (androgen deficiency)? Try to palpate testes in the inguinal canal, realizing that you can't be sure that they aren't ectopic ovaries. Do a pelvic ultrasound and look for a uterus, but still remember that the presence of a uterus only signifies the absence of mullerian duct-inhibiting substance. You can check for SRY gene (note how gene names are always italicized) but we've already seen how this can be misleading (even the Olympic Committee were confused). Plus, do you really want to wait weeks before genetic tests and karyotypes return before letting the parents name their baby? So a simple physical exam and an ultrasound should be your leading diagnostic steps.

If you think the baby is a virilized female, statistically speaking 90% will be because of 21-hydroxylase deficiency. An underdeveloped male, however, is a little tougher to diagnose accurately. There may be defective androgen production or normal levels of androgens (androgen resistence). These will be discussed in another post.

2 comments:

Shadi Tabba said...

Hey....you need to look at it differently. If a baby is lucky to have SRY, then he becomes a male. If not, then the pathway goes to the DEFAULT setting of becoming female. So the female is the basic default set up, and the male is the extra step...

Firas said...

Thanks Shadi for the comment. My aim was to make it easier to remember that SRY (which kind of sounds like "sorry") is responsible for the initiation of the progression towards maleness.