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   The Havoc of an Undetected Extra Chromosome

*By JANE E. BRODY*

Published: August 31, 2004

Sam's parents began to suspect something was not quite right when at age 
2, their son still was not walking and he said nothing that made any sense.

Laboratory and neurological tests showed no abnormalities. But a genetic 
test revealed that Sam's cells contained an extra copy of the X 
chromosome. Instead of having 46 chromosomes, including one copy of each 
of the sex chromosomes, X and Y, the normal complement for a boy, each 
of Sam's cells had 47 chromosomes, with two X's and one Y, a genetic 
abnormality commonly called Klinefelter's syndrome.

        
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A doubling of the X chromosome, according to a government study of 
40,000 infants in the 1970's, occurs once in every 500 to 1,000 male 
births, making it one of the most common genetic abnormalities. It is a 
leading genetic cause of male infertility. Yet nearly two-thirds of boys 
and men who have Klinefelter's do not know it, and many live out their 
lives never suspecting that they have an extra chromosome.

As Sam's mother noted in an interview, doctors, too, are often in the 
dark. "None of our doctors had ever heard of it," she said. "We did a 
lot of research on our own."

Sam is now 13, and through special education services, he has been able 
to keep up academically. His speech is now normal and while he has had 
some social problems, he loves sports and participates in athletics, his 
mother said. As he enters puberty, his levels of testosterone are being 
checked regularly by an endocrinologist. When they begin to drop below 
normal, he will receive regular testosterone treatments.

*Array of Symptoms*

The syndrome was first identified in 1942 by Dr. Harry Klinefelter and 
colleagues at Massachusetts General Hospital in Boston, and its genetic 
root was discovered in the late 1950's. Dr. Klinefelter described 
symptoms that included enlarged breasts, small testes, sparse facial and 
body hair and an inability to produce sperm.

Later studies revealed other common complaints: delayed speech and motor 
development; difficulty learning to read and write; very long legs; a 
rounded body type; decreased muscle mass; a tendency to become 
overweight; an increased risk of diabetes and osteoporosis; a small 
penis; and, eventually, a loss of potency.

While overall intellectual abilities are not affected (the I.Q. scores 
of people with Klinefelter's are only slightly lower than average), XXY 
males often experience deficits in specific cognitive functions, 
including language, concept formation, and problem solving, that are 
similar to those in dyslexic children.

After age 25, about 70 percent of patients complain of decreasing libido 
and potency, and normal beard growth is present in only about a fifth of 
patients, wrote Dr. Fabio Lanfranco, and colleagues at the Institute of 
Reproductive Medicine at the University of Münster in Germany, in a 
recent article in the journal The Lancet.

Depression, difficulty following through on goals, unusual fatigue and 
sudden mood swings also often occur in XXY men and boys. There is, 
however, no increase in psychiatric disturbances, criminal behavior or 
mental retardation.

Many of the symptoms of Klinefelter's, especially those noted at puberty 
and beyond, result from a deficiency of testosterone, which occurs in 
about 80 percent of XXY males after the age of 15. But the expression of 
these symptoms varies widely, which accounts in part for why so many men 
and boys with an extra X chromosome go undetected.

Once the genetic abnormality is diagnosed, many of the symptoms can be 
reversed by regular testosterone treatments starting at puberty and 
continuing for life, but failure of normal sperm production is not yet 
correctable.

Today, the term Klinefelter's syndrome has fallen out of favor because 
its expression is so varied, and most medical researchers now refer to 
affected boys and men simply as XXY males. Genetic studies have also 
revealed many variants of the chromosomal mishap. Some boys are born 
with three or more X chromosomes and one Y, some with two X's and two 
Y's, and some with a combination of normal XY cells and abnormal XXY 
cells. The latter are called genetic mosaics, and they tend to have 
fewer symptoms than boys with only XXY cells.

These unusual combinations most often result from problems during the 
formation of the egg or sperm that result in a failure of the two sex 
chromosomes in a germ cell to separate properly.

*Treatment Can Help*

Early recognition and treatment of Klinefelter's syndrome can 
significantly improve the patient's quality of life and prevent serious 
consequences, Dr. Lanfranco and his team wrote. When testosterone levels 
are low, they said, replacement therapy should be started as early as 
possible. This results in increased masculinity, strength, libido, bone 
mineral density and body hair. It also has a positive effect on mood and 
behavior, improves goal-directed thinking and self-esteem and reduces 
fatigue and irritability.

Testosterone therapy is also beneficial to the cardiovascular system, 
though it has no effect on fertility. For Klinefelter patients with 
bothersome breast development, surgical removal of excess tissue is 
possible.

But long before testosterone replacement is needed, XXY boys can benefit 
from special education classes, speech therapy and social behavior 
training. For those seeking a solution to their infertility, it is now 
possible in some cases to extract sperm directly from the testes and 
insert them into an egg outside the woman's body. After fertilization 
and early embryonic development, the embryos can be checked to be sure 
they too do not contain the XXY defect before inserting them into the 
womb. One expert has reported a live birth rate of 20 percent following 
this procedure in 20 couples affected by XXY infertility.

Melissa Aylstock, the mother of an XXY boy and founder of KS & 
Associates, publishes a newsletter with information about support 
groups. The organization can be reached by writing to 11 Keats Court, 
Coto de Caza, Calif. 92679, or calling toll-free (888) 999-9428. Its Web 
site is www.genetic.org <http://www.genetic.org>.