Two facts about Imelda Garcia struck me when Ellen, our genetics counselor, introduced her. First, she seemed unusually nervous. Her hands were balled tightly into fists and her lips were clenched. Second, she was strikingly attractive, with a tall, well-proportioned body, pretty face, and long, dark hair.
"You seem nervous," I began, thinking that an obvious statement might put her more at ease. She was silent for a moment. I tried again. "What's the matter?"
"I'm supposed to be at school now," she answered. "And if my parents knew I was here, they would be very angry."
"Why would they be angry?" Ellen asked.
"They say, There's nothing wrong with you. They say, God made me this way and nothing can be done to change that. But I don't believe that. What kind of a God would do that?"
"What is the problem?" I asked. She began to cry.
"In the town where I was born, a lot of women have the same problem as I do. They call it 'The Curse of the Garcias' because so many in my mother's family have it. Although all of us look and act like everyone else, we are very, very different."
"In what way?" Ellen asked.
"None of us can bear children. We never even get our period."
As Imelda began telling her story, Ellen recorded the family history. Imelda was the seventh of eight children, and she had lived on a small farm in Mexico until her parents moved the family to New York City five years ago. Two of her older sisters, she said, were also affected. The problem stretched back at least four generations: Three of her mother's five sisters have no children, and two of Imelda's maternal grandmother's four sisters had the condition. Over four generations, I counted a total of 16 childless women. That pattern was already suggesting that the syndrome was linked somehow to a problem on the X chromosome.
"My mother says she can tell from the time a girl is 4 or 5 whether she is cursed or not," added Imelda, "but it isn't until we are teenagers that things begin to change."
"How does she know?" I interrupted.
"She says we are prettier than the other girls. But I know that if I could trade being pretty for being normal, I'd do it in a second. In Mexico, girls are treated like royalty when they get their period. But those of us who aren't able to have children are treated like slaves. We are forced to serve the others, to care for them, cook and clean for them. We can't marry. And then, when we become too old to work, we're banished from the houses of our relatives."
"Is that why your family came to New York?" I asked.
"Yes. My parents wanted to do anything they could to make sure that we wouldn't end up that way. So they gave up everything to move here. Still, they don't want us to talk to doctors. But I've learned in biology class about hormones. I've been thinking this may be an endocrine imbalance."
"Before we can talk about helping you, we have to figure out exactly what's wrong," I responded. "It's certainly possible we'll find out you have a simple problem that can be treated with hormones or some other medication. But it's also possible we'll find a condition we can't fix. Are you willing to go ahead, knowing that we may wind up taking away the hope you have now?"
Imelda considered my question for a few moments before answering. "You're right that I have some hope now. But I want to find out, even if it means I have to accept the fact that nothing can be done to help me."
"All right," I replied. "Let me tell you what we're going to do. First, I'm going to examine you. Then I'm going to take blood for some tests. Those tests may tell us the diagnosis. When we get the test results, we'll talk about what can or cannot be done."
Ellen and I left the room. I asked her what she thought the problem might be. Without hesitation, she replied: "Androgen insensitivity syndrome." I agreed.
In human development, being fe- male is, to use computer terminology, the default. Unless it receives other signals, the embryonic tissue that gives rise to the external genitalia will form itself into normal female structures during the first trimester. Making a male is more complex. A gene called SRY on the Y chromosome must prompt the undifferentiated embryonic gonad to become a testis during the seventh week after conception. That testis must then produce testosterone, one of a class of male hormones called androgens. Next, testosterone molecules must attach themselves to the surface of the individual cells that form the embryonic sex ducts, the structures that ultimately give rise to the external genitalia. If these cells can recognize testosterone, male development proceeds by prompting the female-forming structures, known as müllerian ducts, to degenerate and the male-forming structures, called wolffian ducts, to differentiate into the organs and ducts needed for male development. Any irregularity in this pathway will lead to either incomplete male development or the production of an externally "normal looking" female.
In individuals affected with androgen insensitivity syndrome, also known as "testicular feminization," the first three steps occur normally— individuals inherit an X and a Y chromosome, the SRY gene on the Y chromosome signals the undifferentiated gonads to form into testes, and the testes produce normal amounts of testosterone. But then, because of an error in a gene carried on the X chromosome, the cells that are supposed to bind testosterone to their surface and initiate male development can't recognize it. So, in spite of carrying a Y chromosome and making lots of testosterone, these individuals develop into women who have testes in their abdomen instead of ovaries. Because the male-making effects of testosterone are thwarted, the body converts the hormone to estrogen, so these women tend to develop full figures. Overall, they are perfectly healthy, but the testes can, in rare cases, turn cancerous, so they're usually removed when the patient completes development. At that point, the patient must begin estrogen replacement to avoid entering menopause.
Imelda's exam showed she was not normal in two ways. There was no axillary or pubic hair, and her vagina was very short, ending in a blind pouch. Given her exam and the abundance of affected women in her family history, I was nearly certain that the Garcias' problem resulted from inherited X-linked androgen insensitivity syndrome. But I would need a blood test to confirm the diagnosis. The test indeed showed that Imelda had one X and one Y chromosome in her cells. And her hormone testing showed an extraordinarily high level of testosterone. Her endocrine system was screaming for her body to make a man, but her cells were deaf to those instructions.
Before Imelda returned to discuss the tests, Ellen and I had decided to let Imelda start with her own questions. We agreed that we wouldn't tell Imelda about the results of the genetic test unless she brought it up. Telling a woman she has the chromosome complement of a man can have long-term and far-reaching psychological consequences.
When Imelda arrived, I started by saying, "The tests showed that you have an alteration in one of your genes. This gene is responsible for causing your internal structures to mature."
"Does that mean something is wrong with the gene that causes estrogen to be made?" Imelda asked.
"Not exactly," I replied. "It's the gene that causes the cells of the body to be able to recognize the presence of the sex hormones. Because of the way the gene is altered, your internal structures are unable to recognize hormones. As a result, they did not develop as they should have, and when you're a few years older, you'll need an operation to remove your gonads."
"Does this mean my womb didn't develop?" Imelda asked.
"You mean I can't have children?"
Her eyes filled with tears.
"Imelda, I wish we'd found something that would get better with medication. I'm sorry."
"This doesn't make you any less of a person," Ellen said. "You're not in Mexico now, you're in New York. And in New York, women who can't have children aren't considered useless, hopeless people. You're young, you're smart, and you have your whole life ahead. You can be anything you want to be."
"Except a mother," Imelda added.
"It is true that because of this problem you won't be able to bear children of your own," I said. "But you can always adopt children. And being a mother to an adopted child is just as satisfying as being a mother to a child you've borne yourself."
There was silence in the room for a few seconds. "When I came here last week," Imelda finally said, "you asked if I wanted to go ahead with this, even though there was a chance I'd find out that nothing could be done. Even though it worked out this way, I think I made the right decision."
I was glad she felt that way, but I found this a frustrating message to deliver. In recent years, thanks to the genetic revolution, physicians can discover detailed answers to complex diagnostic questions that used to remain mysteries. But the answers don't necessarily make anything better. In one way or another, we all have to live with who our genes have dictated we are.