A Genetic Enigma
Jack Brans does not recall his childhood fondly.
The New Orleans resident had difficulty concentrating in school and was often disruptive. Frequently depressed, he underwent sharp, violent mood swings.
At puberty, he grew breasts. “When we played any game ‘shirts and skins,’ I always tried very hard to be shirts,” he said. “Gym was a nightmare.”
Ugly varicose veins on his legs meant that he always wore long pants and long socks, never shorts. Tall and gangly, he looked like a basketball player, but was too uncoordinated.
To make matters worse, “I had no sex drive then,” he said in a recent interview. “I didn’t even know what an erection was.”
At the age of 19, an alert physician found that Brans had Klinefelter syndrome, a genetic disorder marked by the presence of an extra sex chromosome. Instead of the normal X and Y sex chromosomes of a male, Klinefelter victims have two Xs and a Y.
As many as one in 400 men worldwide have Klinefelter syndrome, making it the most common chromosomal abnormality--but one of the least well-known.
“It’s much more common than is appreciated,” said Dr. Ronald Swerdloff of the Harbor-UCLA Research and Education Institute in Torrance. “Most physicians know nothing about it.”
Only recently have researchers begun to examine how the presence of an extra X chromosome exerts its many effects. But as they begin to understand it better, it seems likely that the research will provide new information on much broader problems.
“This could give us a lot of insight” into dyslexia and infertility, which are common among Klinefelter victims, noted Swerdloff, one of the leading experts on the syndrome.
The syndrome was identified in 1942 by Dr. Harry Klinefelter and his colleagues at Massachusetts General Hospital, who reported on nine men with enlarged breasts, sparse facial and body hair, small testes and an inability to produce sperm.
By the late 1950s, researchers had discovered that most men with the syndrome had an extra X chromosome, making them XXY instead of the usual XY. A few, however, are XXYY, XXXY or even XXXXY.
The problem arises when cells destined to become either sperm or eggs undergo a process known as meiosis. In this process, the 46 chromosomes (23 pairs) in a normal cell divide to yield two sperm or egg cells, each containing 23 chromosomes. For reasons that are not yet clear to researchers, errors occur in meiosis and an egg ends up with two Xs instead of one, or a sperm ends up XY instead of either X or Y.
Although older mothers have a very slight increased risk of bearing a child with Klinefelter syndrome, there are no other known risk factors.
Some people with the syndrome are diagnosed prenatally, but most are diagnosed either when they enter school, when they pass through puberty or as young adults, Swerdloff said.
In the early school years, many Klinefelter patients have what appears to be attention deficit hyperactivity disorder, often leading to medical tests.
“Many young boys who have been diagnosed with ADD probably have Klinefelter syndrome,” he added.
After puberty, dyslexia is a major problem for most, but not all, Klinefelter boys. “They have a normal IQ, but have severe difficulty with reading and math,” he said. Often, however, they will be remarkably good at music, art or activities involving spatial skills.
“My son can quickly put a [jigsaw] puzzle together looking only at the backs of the pieces,” said Melissa Aylcock, chairman of the support group Klinefelter Syndrome and Associates in Roseville.
The final chance to detect Klinefelter patients is when they go to physicians because of fertility problems. Virtually all men with the syndrome are infertile.
The only treatment currently available is the administration of male hormones, typically testosterone, said Dr. C. Alvin Paulsen of the University of Washington. Most commonly, patients receive a shot of a long-acting form of testosterone every seven to 10 days, but some patients use a testosterone patch that must be replaced daily.
Researchers are now testing a testosterone gel and a tablet that dissolves under the tongue.
Regardless of how it is administered, testosterone restores sexual drive and reduces depression, Paulsen said. Although some Klinefelter patients say that it also improves their learning ability, there is no general proof of that, he added.
Swerdloff is now testing the drug’s effect in boys ages 10 to 12 to see if administering it before the age of puberty will ease their adolescence. “If the effects are positive, we may treat even younger boys,” he said.
If the drug is administered at a young enough age, he speculated, it might allow boys’ brains to develop more normally, minimizing learning disorders.
Researchers’ most urgent concern is to understand how the extra chromosome produces its various effects through the thousand or more genes on the X chromosome.
Those genes, most of whose identities are still unknown, are activated at specific times throughout life when the body needs the enzymes or other proteins for which the genes provide the blueprints. In the case of a Klinefelter male, however, the gene is activated on at least two X chromosomes and the boy (or man) gets a double dose.
Dr. Daniel H. Geschwind, a neurogeneticist at UCLA, has devised a new technique to determine which genes on the chromosome are activated at any given time. He is now attempting to determine causes of dyslexia by comparing Klinefelter patients who do not have dyslexia with those who do.
Other researchers have recently developed a mouse model of Klinefelter syndrome in hopes of learning how the extra chromosome produces infertility.
For Brans, now 33 and entering his senior year at the University of New Orleans, testosterone treatment has dramatically changed his life. “The therapy was really a love potion,” he said. His breasts shrank back to normal. He has taken up swimming, which had interested him as a preteen.
Schoolwork is also much easier, he said, and he really loves to read. “Summer is very boring,” he concluded. “I can’t wait for school to start again.”
(BEGIN TEXT OF INFOBOX / INFOGRAPHIC)
For More Information
Several Web sites provide additional information about Klinefelter syndrome:
https://www.genetic.org is the site for the Klinefelter Syndrome and Associates support group, headquartered in Roseville, Calif.
https://www.nih.gov/nichd/html/news/klinefel.htm is the National Institute of Health’s Web site.
The Klinefelter Syndrome Research Center at Harbor-UCLA Medical Center in Torrance can be contacted through Amy Scott at (310) 222-1866.
