How Klinefelter Syndrome has impacted our family by James G. We recently had a wedding in our family which brought us a new family member with a surprise medical condition. The new couple, both in their late 30’s were anxious to start a family. When they were unsuccessful, they sought help from fertility experts. He was told he had a genetic condition called Klinefelter Syndrome. Since he had mild symptoms it had not been detected earlier in his life. It turns out that he had an extra X chromosome. None of us had ever heard of this kind of genetic condition. We all read up on it right away. It turns out that even though he has the extra X chromosome he cannot pass it on to his children. One of his symptoms is a low sperm count. So, they are using IVF fertilization to get pregnant, and we all have our fingers crossed that they are successful and we can welcome a new baby into the family, as well. Here's some of what we found out:
What is the X chromosome? The X chromosome is one of the two sex chromosomes in humans (the other is the Y chromosome). The sex chromosomes form one of the 23 pairs of human chromosomes in each cell. The X chromosome spans about 155 million DNA building blocks (base pairs) and represents approximately 5 percent of the total DNA in cells. Each person normally has one pair of sex chromosomes in each cell. Females have two X chromosomes, while males have one X and one Y chromosome. Early in embryonic development in females, one of the two X chromosomes is randomly and permanently inactivated in cells other than egg cells. This phenomenon is called X-inactivation or Lyonization. X-inactivation ensures that females, like males, have one functional copy of the X chromosome in each body cell. Because X-inactivation is random, in normal females the X chromosome inherited from the mother is active in some cells, and the X chromosome inherited from the father is active in other cells. Some genes on the X chromosome escape X-inactivation. Many of these genes are located at the ends of each arm of the X chromosome in areas known as the pseudoautosomal regions. Although many genes are unique to the X chromosome, genes in the pseudoautosomal regions are present on both sex chromosomes. As a result, men and women each have two functional copies of these genes. Many genes in the pseudoautosomal regions are essential for normal development. Identifying genes on each chromosome is an active area of genetic research. Because researchers use different approaches to predict the number of genes on each chromosome, the estimated number of genes varies. The X chromosome likely contains 800 to 900 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body. Genes on the X chromosome are among the estimated 20,000 to 25,000 total genes in the human genome.
How are changes in the X chromosome related to health conditions? Many genetic conditions are related to changes in particular genes on the X chromosome. This list of disorders associated with genes on the X chromosome provides links to additional information. Changes in the structure or number of copies of a chromosome can also cause problems with health and development. The following chromosomal conditions are associated with such changes in the X chromosome.
Klinefelter syndrome Klinefelter syndrome is caused by the presence of one or more extra copies of the X chromosome in a male's cells. Extra genetic material from the X chromosome interferes with male sexual development, preventing the testes from functioning normally and reducing the levels of testosterone (a hormone that directs male sexual development). A shortage of testosterone can lead to delayed or incomplete puberty, genital abnormalities, breast enlargement (gynecomastia), reduced facial and body hair, and an inability to have biological children (infertility). Children with Klinefelter syndrome may also have learning disabilities, delayed speech and language development, and a shy and unassuming personality. Typically, people with Klinefelter syndrome have one extra copy of the X chromosome in each cell, for a total of two X chromosomes and one Y chromosome (47,XXY). Less commonly, affected individuals may have two or three extra X chromosomes (48,XXXY or 49,XXXXY). As the number of extra sex chromosomes increases, so does the risk of learning problems, intellectual disability, birth defects, and other health issues. Some people with features of Klinefelter syndrome have the extra X chromosome in only some of their cells; in these individuals, the condition is described as mosaic Klinefelter syndrome (46,XY/47,XXY). Individuals with mosaic Klinefelter syndrome may have milder signs and symptoms, depending on how many cells have an additional X chromosome. http://ghr.nlm.nih.gov/chromosome/X
What is Klinefelter syndrome? Klinefelter syndrome is a chromosomal condition that affects male physical and cognitive development. Its signs and symptoms vary among affected individuals. Affected individuals typically have small testes that do not produce as much testosterone as usual. Testosterone is the hormone that directs male sexual development before birth and during puberty. A shortage of testosterone can lead to delayed or incomplete puberty, breast enlargement (gynecomastia), reduced facial and body hair, and an inability to have biological children (infertility). Some affected individuals also have genital differences including undescended testes (cryptorchidism), the opening of the urethra on the underside of the penis (hypospadias), or an unusually small penis (micropenis). Older children and adults with Klinefelter syndrome tend to be taller than their peers. Compared with unaffected men, adults with Klinefelter syndrome have an increased risk of developing breast cancer and a chronic inflammatory disease called systemic lupus erythematosus. Their chance of developing these disorders is similar to that of women in the general population. Children with Klinefelter syndrome may have learning disabilities and delayed speech and language development. They tend to be quiet, sensitive, and unassertive, but personality characteristics vary among affected individuals.
How common is Klinefelter syndrome? Klinefelter syndrome affects 1 in 500 to 1,000 newborn males. Most variants of Klinefelter syndrome are much rarer, occurring in 1 in 50,000 or fewer newborns. Researchers suspect that Klinefelter syndrome is under-diagnosed because the condition may not be identified in people with mild signs and symptoms. Additionally, the features of the condition vary and overlap significantly with those of other conditions.
What are the genetic changes related to Klinefelter syndrome? Klinefelter syndrome is a condition related to the X and Y chromosomes (the sex chromosomes). People typically have two sex chromosomes in each cell: females have two X chromosomes (46,XX), and males have one X and one Y chromosome (46,XY). Most often, Klinefelter syndrome results from the presence of one extra copy of the X chromosome in each cell (47,XXY). Extra copies of genes on the X chromosome interfere with male sexual development, often preventing the testes from functioning normally and reducing the levels of testosterone. Most people with an extra X chromosome have the features described above, although some have few or no associated signs and symptoms. Some people with features of Klinefelter syndrome have more than one extra sex chromosome in each cell (for example, 48,XXXY or 49,XXXXY). These conditions, which are often called variants of Klinefelter syndrome, tend to cause more severe signs and symptoms than classic Klinefelter syndrome. In addition to affecting male sexual development, variants of Klinefelter syndrome are associated with intellectual disability, distinctive facial features, skeletal abnormalities, poor coordination, and severe problems with speech. As the number of extra sex chromosomes increases, so does the risk of these health problems. Some people with features of Klinefelter syndrome have the extra X chromosome in only some of their cells; in these individuals, the condition is described as mosaic Klinefelter syndrome (46,XY/47,XXY). Individuals with mosaic Klinefelter syndrome may have milder signs and symptoms, depending on how many cells have an additional X chromosome.
Can Klinefelter syndrome be inherited? Klinefelter syndrome and its variants are not inherited; these chromosomal changes usually occur as random events during the formation of reproductive cells (eggs and sperm) in a parent. An error in cell division called nondisjunction results in a reproductive cell with an abnormal number of chromosomes. For example, an egg or sperm cell may gain one or more extra copies of the X chromosome as a result of nondisjunction. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have one or more extra X chromosomes in each of the body's cells. Mosaic 46,XY/47,XXY is also not inherited. It occurs as a random event during cell division early in fetal development. As a result, some of the body's cells have one X chromosome and one Y chromosome (46,XY), and other cells have an extra copy of the X chromosome (47,XXY). http://ghr.nlm.nih.gov/condition/klinefelter-syndrome
Several men with a serious genetic fault have been able to father normal children thanks to the controversial IVF technique known as ICSI. Men with Klinefelter's syndrome have an extra X chromosome. While many don't know about the condition until they discover they're infertile, others have symptoms such as mental retardation. Since the men cannot produce viable sperm, for the past few years Zev Rosenwaks's team at Cornell University has been retrieving immature sperm directly from their testicles. The best-looking ones are used to fertilize eggs from their partners using ICSI, or intracytoplasmic sperm injection, in which a sperm is injected into the egg. Rosenwaks told a conference in Montreal last month that 9 of the 15 patients with Klinefelter's treated this way have managed to have children. All 14 babies have a normal number of chromosomes. http://www.newscientist.com/article/mg17423482.100-men-with-extra-x-chromosome-father-normal-children.html
