Current views on the genetics of Kallmann Syndrome and

Hypogonadotrophic Hypogonadism.

In the past Kallmann Syndrome (KS) and Hypogonadotrophic Hypogonadism (HH) were thought to be caused by single gene defects.

To date there have been 7 different genes on 7 different chromosomes that have been implicated in causing either or both KS or HH.

It has been recognised that different people with the same detectable gene defect for KS or HH show different symptoms. Even within family groups with the same inherited gene defect there is a variation in symptoms seen.

Recent evidence presented by researchers from Boston, USA (Dr Nelly Pitteloud)and Newcastle, UK (Dr Richard Quinton) has presented a new method to explain the inheritance of KS and HH.

It is proposed that some KS and HH cases are caused by a combination of gene defects on two different genes at the same time. This digenic inheritance of two separate gene defects would help to explain the range of symptoms seen in KS and HH cases. Mild or more severe symptoms would depend on what 2 genes are involved and the type of defect in each of the genes.

This has implications for the prediction of inheritance of KS and HH. On a single gene model it was fairly straight forward to give a 0%, 25%, 50% or 100% chance of passing on a gene defect. With 2 genes involved the situation becomes more complex and it becomes increasingly difficult to predict the chances of passing on KS or HH.

-------------------------------------------------------------------------

The 7 genes currently thought to cause KS or HH:

FGFR-1 (8p 12) Fibronectin growth factor receptor.

NELF (9q 34.3) Nasal embryonic GnRH factor.

KAL-1 (Xp 22.32) Anosmin

PROK2 (3p 21.1) Prokineticin (G protein 73)

PROKR2 (20p 12.3) Prokineticin receptor

GNRHR (4q 21.2) GnRH receptor

GPR54 (19p 13.3) G-protein 54 receptor (also called KISS-2 receptor)