N.Y. Times

August 31, 2004

PERSONAL HEALTH

The Havoc of an Undetected Extra Chromosome

By JANE E. BRODY

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.

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

Copyright 2004 The New York Times Company