Q16. What are "genes" and how do they relate to Kallmann syndrome ?

The genetics of Kallmann syndrome and other forms of congenital hypogonadotropic hypogonadism is complex. This is partially due to the fact that there is no one single genetic cause for all the cases and about half the cases still have an unknown genetic origin. In addition it is now thought that Kallmann syndrome and CHH is more likely to be a two gene defect condition rather than just one.

The human body is made up of thousands of millions of microscopic cells, virtually all of which have a central nucleus, each containing tiny thread-like "packages" of information known as chromosomes (see Figure 15a). Chromosomes are made up of even smaller units called genes.

Genes contain packets of code or information, which when read correctly produce the physical characteristics, features and appearance of the person. Genes are comprised of strands of DNA, often called the "building block" of life. 

Virtually every cell in the body will have 22 pairs of identical chromosomes (called autosomes) and a pair of sex chromosomes. Males will have an X and Y chromosome and females will have two identical X chromosomes. These chromosomes normally align as identical pairs, so in humans that is normally 22 pairs plus either XX or XY to give 46 chromosomes in total inside the vast majority of cells.

These chromosomes will contain thousands of genes, all with a specific job to do. Some genes are absolutely vital for life, others have unknown function, some genes have to rely on the activity of other genes in order to function correctly. 

The entire genetic code which makes an individual unique is contained within the genes enclosed in the 23 pairs of chromosomes (22 autosomes + either XX or XY). The entire genetic code is called the genome.

As seen in Fig 15b the gamete cells, the sperm or the egg, only contain one copy of each chromosome. So in females egg cells will contain 22 single, un-paired autosomes plus one X chromosome. In males sperm cells will contain 22 single, un-paired autosomes plus either one X or one Y chromosome. 

A new individual is normally created when an egg containing one X chromosome combines with the sperm cell containing either an X or Y chromosome. The 23 chromosomes in each cell join together in the new cell (called a zygote) which then divides and grows into a new individual.

There are genetic conditions which arise when this transfer of chromosomes does not go to plan and the zygote is left with the wrong number of chromosomes. There are conditions where too many copies of a chromosome are transferred or no copy of a chromosome is transferred. 

Klinefelter syndrome and Turner syndrome are examples where the number of sex chromosomes transferred is incorrect. In Klinefelter syndrome you get an extra copy of the X chromosome (XXY) In Turner syndrome you get one copy of the X chromosome but the additional sex chromosome is missing (X-) instead of (XX).

It is estimated that one in 160 live births will have a chromosomal abnormality. The abnormality can be in the sex chromosomes as in Turner or Klinefelter or in the autosomes.

There are other conditions where an extra copy of an chromosome is transferred. The classic example of this is Down syndrome where an individual will have an extra, a third, copy of the chromosome number 21. 

Kallmann syndrome and other forms of congenital hypogonadotropic hypogonadism are not chromosomal abnormality conditions.

Individuals with Kallmann syndrome and CHH are almost invariably born with the correct number of chromosomes, 46 XY for males and 46 XX for females. The underlying cause of Kallmann syndrome and CHH is the transfer or inheritance of specific genes contained within the chromosomes.

Sometimes doctors will ask for a karyotype test to be done in cases of abnormal pubertal development. This is a relatively straight forward test which will detect the number of chromosomes present and which sex chromosomes are present. A karyotype test will be able to detect a case of Klinefelter syndrome (47XXY) or Turner syndrome (45X-).

In Kallmann syndrome and CHH the karyotype will be normal, with 46XY or 46 XX. This is due to the problem being at the gene level not at the chromosomal level.