When Genetics Pulls A Fast One, Gender Identification Can Become Complicated

Consider this a sort of Public Service Announcement about the nuances of prenatal testing (and, in an odd way, about the selection of individual pronouns).

I became interested in anomalies of the human sex chromosomes, X and Y, as a medical student, when I had a patient with a rare genetic condition that gave rise to a syndrome called “androgen insensitivity” or “testicular feminization.” It is caused by either of two types of mutations on the X chromosome. (Recall that females are generally XX, while males are XY.)

So, while normally, people with one X and one Y chromosome in every somatic cell (and who are designated “XY”) would be males, the mutations distort development. One mutation causes a deficiency of the receptor for the hormone dihydrotestosterone (DHT), which promotes male characteristics; in the other, the receptor is apparently present, but the receptor-DHT complex is inactive. Thus, in either case, the hormone cannot perform its normal actions, which would give rise to a male-appearing fetus, so the fetus is phenotypically a female.

My patient was genetically male (XY), but because of the mutation, his cells were unable to respond to DHT in utero, the result of which was the birth of a person who became a normal-appearing woman with adequate breast development, normal female external genitalia but a vagina of less than normal depth, absent uterus, sparse pubic and axillary hair, and the absence of menstrual periods.

(This situation adds a new wrinkle to current confusion about appropriate pronouns.)

Some form of testicular feminization occurs in about one out of 20,000 births and can be incomplete (giving rise to various sexual ambiguities) or complete (the genetic male appears to be a woman). Even many physicians have never heard of it, so I was surprised to see a case of it depicted several years ago on the British TV series, “Call the Midwife.” There is a description of the episode here.

Testicular feminization is the kind of abnormality that can be detected by prenatal genetic tests, which raises various medical, ethical, and moral issues -- such as whether to abort the fetus -- because there is currently no treatment for it. 

Far more common are variations in sex chromosomes where people have an extra or missing entire X or Y.  These are the most frequent chromosomal anomalies, occurring in approximately one in 400 births.  However, most people affected are unaware that they have them, because the anomalies are not life-disrupting and, unlike testicular feminization, seldom give rise to telltale characteristics, signs, or symptoms.

Thus, because of the confusion and anxiety that can ensue when a person (or parent) learns of the genetic anomaly, perhaps knowing about the diagnosis might be worse than the “disease” itself.

The first noninvasive prenatal screening (NIPS) appeared just over a decade ago. The first-trimester blood tests that became available in 2011 to detect Down syndrome have vastly expanded their repertoire, gradually adding more conditions, including atypical numbers of sex chromosomes, to their panel.  

In 2020, the American College of Obstetricians and Gynecologists endorsed conducting noninvasive prenatal screening during all pregnancies.  Their website describes the categories of genetic disorders that are possible:

Aneuploidy is a condition in which there are missing or extra chromosomes. In a trisomy, there is an extra chromosome. In a monosomy, a chromosome is missing. Inherited disorders that are caused by changes in genes are called mutations. These include sickle cell disease, cystic fibrosis, Tay-Sachs disease, and many others.

Testicular feminization is in the category of abnormalities caused by mutations.

Although parents-to-be might think the test is intended primarily to rule out Down syndrome or more severe abnormalities, as noted above, other findings might be detected, many of them inconsequential.  Even so, the finding of sex chromosome abnormalities often precipitates a decision to terminate the pregnancy, particularly in younger couples.

In view of the complexity and importance of the information derived from prenatal testing, parents-to-be would be wise to obtain genetic counseling to provide information about how genetic abnormalities might affect them and their family, if at all. The genetic counselor or other qualified healthcare professional collects personal and family health history, which is used to estimate how likely it is that the fetus has a serious genetic condition and to recommend which genetic tests might be appropriate.

This is truly a situation in which, as the saying goes, knowledge is power. Expectant parents should obtain counseling to learn what the future may hold.