Sometimes children are born with gender ambiguity; without a scrotum and with a very small penis, or with a large clitoris. Agneta Nordenskjöld and her colleagues are studying the genetics behind why some boys’ genitals do not develop like they should.
The first question parents get when a child is born is often: ”What did you get?”. Around 15 parent couples per year in Sweden cannot answer that question without a medical investigation, because nobody can quickly determine which gender their child is. Is it a boy with a very small penis? Or a girl with a large clitoris?
Some parents go underground until the investigation is finished in order to avoid having to answer the question ”what did you get”. Among other things, the doctors check if the child has ovaries or testicles and if it has two X-chromosomes or one X-chromosome and one Y-chromosome.
Many parents of children who are born with gender ambiguity also wonder about the risk for the subsequent sibling. These problems are in fact often hereditary. The parents’ concern is not only due to the emotional stress at birth, but also because the little baby may need to undergo several operations already during its first year. A proper molecular diagnosis can help the parents in their decision. That is why the genetics behind the abnormality is mapped by Agneta Nordenskjöld and her colleagues in the so called DSD team at the Astrid Lindgren Children’s Hospital. DSD stands for Disorders in Sex Development.
"If we know which genes are causing the problem, we can give proper information to the parents", Agneta Nordenskjöld says.
If the cause is a change in a gene located on the X-chromosome, for example, the parents can get the information that the risk is one in two that the next XY-fetus is born without a fully developed penis. If the gene is located on any other chromosome and if it is not dominant, the risk is lower.
A boy with an undeveloped penis often has severe so called hypospadias, see the picture to the right. In its mild form, hypospadia results in the urethra being too short, ending only part way up on the penis. In its severe form, however, penis can become so small and curved that the urethra stops in the pelvic floor. Sometimes the testicles remain inside the body, and the boy is born without a scrotum.
Girls can also be born with ambiguous gender. They may, for example, have been exposed to too much male sex hormone during their time in the womb. This often results in a large clitoris and a boyish appearance of the genitals. Scientists know quite a lot about the genes behind this, and the parents can in a majority of cases find out how high a risk a second child would run in getting the same affliction. Moreover, there is a possibility to perform so called prenatal diagnostics (find out if the fetus has inherited the disorder).
But when it comes to the boys’ problem, the picture is more muddled for the scientists. In order to find the genes behind hypospadia, Agneta Nordenskjöld and her colleagues have studied almost 100 families where fraternal pairs or other related pairs were born with hypospadia. First, they honed in on six different interesting areas on the body’s 46 chromosomes. From these areas, they sifted out four. In the two remaining areas, there are two different candidate genes which deal with the sex hormone metabolism.
"But we do not know yet exactly what these genes do", Agneta Nordenskjöld says.
Agneta Nordenskjöld and her colleagues are also investigating the genetics behind bladder exstrophy; children who are born with their bladder open on their tummy. There are signs that bladder exstrophy is hereditary. So far, they have made some interesting findings, but this line of research is still in its infancy.
Another section of Agneta Nordenskjöld’s research is long term follow-ups of people who are born with gender ambiguity. From past experiences, doctors have learned not to carry out too major surgical operations. A few decades ago, the child’s gender was determined by how great the prospects were to create a functional penis. If the surgeons thought it was possible, the child became a boy. If not, the testicles were removed and the child became a girl. Nowadays, Agneta Nordenskjöld and her colleagues preserve as much as possible of the child’s original genitalia.
"If a girl has a large clitoris, for example, it is not always a good idea to remove the corpus cavernosum [the sponge-like regions of erectile tissue around penis or clitoris]. Instead, one option is to hide clitoris underneath the skin. It is important to get a cosmetically satisfying result, but you have to leave a way out. We try to avoid surgical procedures which cannot be reversed. We do not want them to one day accuse neither us nor their parents for having destroyed something", Agneta Nordenskjöld said.
On the other hand, not doing surgery is not an option, Agneta Nordenskjöld asserts. This could result in, for example, difficult situations in the shower after PE. That is one experiment Agneta Nordenskjöld does not want to put the children through. Her long term follow-ups on children with gender ambiguity shows among other things that girls who have had too much male sex hormone often (but certainly not always) chose what are traditionally more male jobs. Now she is looking into quality of life for men who were born with severe hypospadia, for example if their choice of profession has been affected at a group level, in order to study the hormonal effect on behaviour.
Furthermore, she continues to investigate in more detail the genetic changes she has connected to sever hypospadia. When she and her colleagues learn more about these, they can better understand how the abnormality arises and help parents who would like to know how great the risk is for the next child to also be born with gender abnormality.
Text: Ann Fernholm