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Differences in gene defects causing Kallmann syndrome or CHH cases.

May 7, 2016



Diagram showing the migration of GnRH releasing neurones during early brain development & the location of the actions of the genes associated with KS / HH.

Diagram showing the migration of GnRH releasing neurones during early brain development & the location of the actions of the genes associated with KS / HH.


This diagram (with thanks to Prof Nelly Pitteloud, CHUV) shows the schematic layout of the causes of Kallmann syndrome or congenital hypogonadotropic hypogonadism with the migration of GnRH neurones and some of the gene defects that are linked to the two conditions.

Listed are 16 of the currently 25 known genes, defects in which, are known to cause cases of KS or CHH and the location where these genes have an effect.

Seven of the genes (KAL-1, FGFR1, FGF8, PROKR2, PROK2, CHD7, NELF) are involved in the development and migration of the GnRH releasing neurones. These neurones are supposed to migrate along the same channel as the olfactory axons from a structure called the olfactory placode until they meet up with the hypothalamus.

This normally takes place around week 10 to 14 of embryonic development. If one of these genes are affected the passage of both the olfactory axons and GnRH neurones can be blocked which results in the anosmia and GnRH deficiency seen in Kallmann syndrome. The olfactory bulb is not fully formed, which can be observed in an MRI scan and the hypothalamus is unable to release GnRH which prevents puberty and the reproductive cycle from occurring.

The remaining genes listed (DAX1, PC1, LEPR, LEP, KISS1R, FGFR1, PROKR2, PROK2, TACR3, TAC3, GNRH1) are involved in the correct regulation of GnRH secretion from the hypothalamus. Some of the genes listed affect both the migration of the GnRH neurones and the regulation of the GnRH release.

The genes that are involved purely in the regulation of GnRH secretion have no effect on the migration of the GnRH neurones or olfactory axons, so the olfactory bulb is correctly formed which results in a normal sense of smell, this condition is called congenital hypogonadotropic hypogonadism (CCH).

The hypothalamus has to release GnRH in a specific pulsatile manner in order for the pituitary gland to be able to release FSH / LH which will initiate puberty and the reproductive cycle. If this pulsatile release of GnRH is impaired it will prevent the correct release of FSH / LH (known together as the gonadotropins) and the reproductive cycle will break down.

One final gene listed is GNRHR. A defect in this gene prevents the pituitary gland from being able to recognise the GnRH secreted from the hypothalamus so it also prevents the release of LH and FSH from the pituitary gland.

There are more gene defects that can be added to this diagram with over 25 known implicated genes at the time of writing.

Knowledge of which genes are involved in a particular case can give an indication on the possible success rate of fertility treatments using GnRH therapy or gonadotropin therapy. 

Research is being carried out into the control mechanisms that lead to the control of GnRH from the hypothalamus and what external signals have an influence on the hypothalamus. This might in time lead to the development of medications that can restore the function of the hypothalamus, restore correct pulsatile GnRH release and “reverse” a case of Kallmann syndrome or CHH, which is known to happen in about 20% of cases at present.

Neil Smith.
May 2016.

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