Pathophysiology
Kallmann syndrome (KS) and other forms of hypogonadotropic hypogonadism (HH) can be classed as pituitary or endocrine disorders. While the end result is a failure of puberty and the secondary sexual characteristics to develop the underlying cause of the disorder is located between two endocrine glands located within the brain.
The hypothalamus gland and the pituitary gland can be seen as the control stations for all the hormonal activity throughout the body. The glands control a number of different hormones with varying effects around the body. KS/HH results from the disruption in the communication between the hypothalamus and pituitary in regard to one set of hormones only. All the other actions of the hypothalamus and pituitary glands remain unaffected, unless there is an underlying condition other than just KS/ HH which is causing the same symptoms.
Normally the hypothalamus releases a hormone called gonadotropin releasing hormone (GnRH), sometimes called luteinizing hormone release hormone (LHRH) instead. This GnRH is released from the hypothalamus in set intervals throughout the day via the hypophyseal portal system and acts on the anterior pituitary gland causing it to release two hormones called gonadotropins. These hormones are luteinizing hormone (LH) and follicle stimulating hormone (FSH). These hormones have a direct action on the testes in men and ovaries in women. These hormones are essential for stimulating the secondary sexual characteristics seen at puberty and then maintaining the normal sexual function of both men and women including maintaining the correct levels of the sex steroids testosterone in men and oestrogen and progesterone in women.
Figure 5 shows the normal hormonal control of puberty from the hypothalamus down to the testes or ovaries and their negative feedback mechanisms. The negative feedback control allows just the right amount of hormone to be released according the needs of the body at that time.
Figure 7 shows the effect of the interruption of GnRH hormone release from the hypothalamus on the subsequent inability of the testes and ovaries to function correctly at puberty as seen in cases of KS/HH. In most cases of KS/HH the testes and ovaries are able to function correctly, but fail to do so because they have not had the correct hormonal signals.
In KS/HH the release of GnRH is either totally blocked or vastly reduced. The GnRH is released by the hypothalamus by specialised nerve cells or neurones. During development of the brain in the first 10 weeks of development these GnRH releasing neurones migrate from their original source and end up inside the hypothalamus.
The GnRH neurones originate in an area of the developing brain called the olfactory placode; they then pass through the cribriform plate and into a structure called the olfactory bulb. From there they migrate into what will be become the hypothalamus. The olfactory bulb is where the sense of smell is generated. Any problems with the development of the olfactory bulb will prevent the progression of the GnRH releasing neurones through it. If the GnRH releasing neurones are prevented from reaching the hypothalamus no GnRH will be released, so in turn no FSH or LH will be released which results in the failure of puberty and the production of testosterone in men and oestrogen and progesterone in women.
In Kallmann syndrome the olfactory bulb is missing or not fully developed which gives rise to the additional symptom of lack of sense of smell (anosmia) or vastly reduced sense of smell (hyposmia). In other forms of HH the olfactory bulb develops correctly, so there is a normal sense of smell but the migration of the GnRH releasing neurones is affected elsewhere and still gives rise to no GnRH being released at the correct time.
However, this connection between the olfactory bulb and GnRH neuron cells is not as tightly coupled as first thought. The majority of congenital anosmics with no olfactory bulbs do not have reproductive hormone deficiencies. In the same family with the same KS/HH gene(s), some members may have KS with no sense of smell, others may have IHH with a sense of smell and others may have isolated anosmia and no hormone deficiencies.
The majority of the genes that have been associated with causing cases of KS or HH play a part in either the generation, migration or activity of these GnRH releasing neurones and their ability to stimulate FSH and LH production.
| OMIM | Name | Gene | Locus | Description |
|---|---|---|---|---|
| 308700 | KAL1 | KAL1 | Xp22.3 | Kallmann syndrome can be inherited as an X-linked recessive trait, in which case there is a defect in the KAL1 gene, which maps to chromosome Xp22.3. KAL encodes a neural cell adhesion molecule, anosmin-1. Anosmin-1 is normally expressed in the brain, facial mesenchyme, mesonephros and metanephros. It is required to promote migration of GnRH neurons into the hypothalamus. It also allows migration of olfactory neurons from the olfactory bulbs to the hypothalamus. |
| 147950 | KAL2 | FGFR1 | 8p11.2-p11.1 | An autosomal dominant gene on chromosome 8 {8p12} (KAL-2 or FGFR-1 (fibroblast growth factor receptor 1)) is thought to cause about 10% of cases. |
| 244200 | KAL3 | PROKR2 | 20p13 | An additional autosomal cause of Kallmann syndrome has been reported by mutations in the prokineticin receptor-2 gene (PROKR2)(KAL-3) at position 20p13 and its ligand prokineticin 2 (PROK2)(KAL-4) at position 3p21.1. It was noted that mutations in these genes brought about various degrees of olfactory and reproductive dysfunction, but not the other symptoms seen in KAL-1 and KAL-2 forms of Kallmann Syndrome. The authors of the paper suggested that up to 30% of all Kallmann Syndrome cases can be linked to known genetic mutations. |
| 1527600 | GnRH1 | GnRH1 | 8p21-11.2 | Ligand for the GnRH receptor GnRH11527600 at locus 4q21.2. Binding allows FSH/LH secretion by the pituitary gland. Known to cause IHH and partial IHH. |
| 162330 | TAC3 | TAC3 | 12q13-21 | Ligand for the TAC receptor TACR3 162332 at locus 4q25. Signalling peptide, crucial for GnRH secretion. Known to cause severe IHH with high incidence of micropenis. Known to be one of the genes that have shown a higher rate of reversible IHH than other genes. |
| 164160 | LEP | LEP | 7q31.2 | Ligand for the receptor LRPR. Involved in pulsatile GnRH secretion. |
| 608137 | NELF | NELF | 9q34.3 | Not associated with ligand/receptor binding. Associated with the migration of the olfactory and GnRH neurones during development. |
| 608892 | CHD7 | CHD7 | 8q12.1 | Not associated with ligand/receptor binding. Associated with original generation of GnRH and olfactory neurones. Strongly associated with CHARGE syndrome. |
| 300473 | DAX1/NROB1 | DAX1 | Xp21.3-21.2 | Nuclear receptor with no known ligand. Known to be a transcription inhibitor. Thought to cause x-linked recessive forms of IHH in both males and occasionally females. Known to cause pubertal delay in females. |
| 603286 | KiSS1 | KiSS-1 | 1q32.1 | Ligand for receptor KiSS1R 604161 at locus 19p13.3 Peptide produced by the hypothalamus, essential for pulsatile GnRH secretion. Known to cause IHH, thought to be involved in the timing of the onset of puberty. |
A report published in 2007 by Dr Nelly Pitteloud and Dr Richard Quinton highlights a possible digenic model for Kallmann syndrome and other forms of hypogonadotrophic hypogonadism. The possibility of two separate gene defects working in combination would account for the variation of symptoms seen with people with Kallmann syndrome, even within family groups.
The genetics of Kallmann syndrome and other forms of hypogonadotrophic hypogonadism is still far from clear with around 70% of cases still with an unknown genetic origin.
Further research published by Anna Mitchell et al. has highlighted the fact that the number of gene loci known to cause cases of Kallmann syndrome and HH have increased to ten. The paper highlights the broad spectrum of physical symptoms both reproductive and non-reproductive that can occur between cases of Kallmann syndrome and HH, even within the same family group.
Read more about this topic: Kallmann Syndrome