Current view on inheritance of Kallmann's / HH.

Kallmann's and HH are genetic conditions because they are present from birth and arise from a gene defect. However, unlike a lot of genetic conditions there is no one particular gene that is known to cause Kallmann's or HH. There have been quite a few candidate genes proposed over the years, occurring on a number of different chromosomes. This means there is no one genetic screening test at present that can indicate the likelihood of an offspring having Kallmann's or HH. This may change in the future as more cases come forward and more genes are studied.

Certain genetic conditions such as Turner's syndrome or Klinefelter's syndrome are caused by the presence of extra chromosomes or by the absence of one. These can be tested for quite easily, even before birth, by taking a small sample of cells and counting the number of chromosomes present (karyotype).

Certain genetic conditions like cystic fibrosis have a definite genetic cause. There is one gene on chromosome 7, where if defective in both copies can in the majority of cases, lead to the development of the disease. This gene can be screened for very early in life and an early diagnosis made.

Currently this cannot happen with Kallmann's or HH due to the lack of a single gene defect that covers the range of conditions. It would be impossible to screen for every gene in this list. Sometimes the defect is very large, as when the whole gene is missing, these are relatively easy to detect. However, as a defect could be a point mutation, one very small defect in a very big gene, these defects are very difficult to detect, and are not normally suitable for screening tests.

Table of current candidate genes in cases of Kallmann's or HH

Gene Location Product Type

KAL-1	Xp22.3	x-linked Kallmann's. Produces anosmin-1, which allows the migration of nasal and GnRH producing nerve cells in the developing brain,	x-linked recessive	point mutation or complete gene deletion. Causes approx 10% of all Kallmann's cases *
KAL-2 (FGFR1)	8p12	HH / Kallmann's. Produces a receptor for fibroblast growth factor.	autosomal dominant	loss of function mutation. Causes around 10% of Kallmann's cases *
GPR-54	19p13.3	HH with normal sense of smell. Possibly a puberty 'activation' gene.	autosomal recessive	homozygous mutation
DAX-1	Xp21	HH associated with congenital adrenal hypoplasia.	x-linked recessive	Usually presents with CAH shortly after birth.
GnRH-R	4q21.2	HH, GnRH receptor defect	autosomal recessive	Loss of function mutation. Causes 5 to 15% of HH cases
FSH-b	11p13	isolated FSH deficiency	autosomal recessive	homozygous mutation
LH-b	19q13.32	isolated LH deficiency	autosomal recessive	homozygous mutation
KISS	1q32-41	HH. KiSS peptide, possibly works in conjunction with GPR-54 as a puberty regulator	autosomal recessive	homozygous mutation. Suspected but not fully investigated relationship between KiSS and GPR-54.
NELF	9q34.3	HH	autosomal recessive	homozygous mis-sense mutation. Suspected, but yet to be confirmed.

*A recent study proposed the possibility of a direct linkage in the action of these two genes, and a combination of defects in both genes could lead to 40 to 50% of all HH cases.

The degree gene defect or mutation with these two genes may lead to the broad range of symptoms seen in HH cases. Some family studies have shown a marked variation in the type of HH inherited.

Delayed puberty + anosmia (classic Kallmann's) à normal puberty + anosmia

Some of these causes of HH are very rare and may only be based on the results of a very small number of patients or family groups.

A large proportion of Kallmann's or HH cases can still be classed as 'isolated' or 'sporadic'. However these terms are misleading, an isolated case may be caused by a first example of a mutation in a gene and could still be inherited. It is safer to assume that any case of KS or HH has the potential to be inherited, and in some cases there could be a 50% chance of it occurring.

x-linked Kallmann's is the most widely studied, but it only forms a small percentage of the total Kallmann's or HH cases. It is the easiest to pick up because of the very high incidence of the combination of anosmia, 'mirror' movements of the hands and cryptorchidism (undescended testes) found in all cases.

Two of the major candidate genes lie on the x-chromosome. Females have two copies of the x-chromosome and hence 2 copies of the KAL-1 and DAX genes. If one is affected, that gene is switched off and the other copy is used instead. This cannot occur in males who only have one copy of the gene; this gives rise to the higher incidence of Kallmann's and HH seen in men than women.

The gene KAL-1 codes for an adhesion protein known as anosmin-1. It is involved in the migration of GnRH producing and olfactory (nasal) nerve cells within the fetal brain early in development. Without this adhesion molecule the GnRH releasing cells are unable to migrate to the hypothalamus and the olfactory neurons are not able to migrate to the olfactory bulb.

In normal development both the olfactory neurons and GnRH releasing neurons originate from the same location and migrate to their correct final position under the influence of various adhesion proteins and other associated proteins. The distance these neurones have to migrate is very small, less than the thickness of a 10p piece. However in order for the migration to occur the correct conditions are required and if there is a problem with the conditions then the migration may not take place fully or not at all.

In non-Kallmann's HH cases the progress of the olfactory neurons is not affected as much or at all. This gives rise to a normal or slightly reduced sense of smell.

This migration occurs within the first few weeks of fetal development, probably within the first 4 to 5 weeks of fetal growth and most likely completed by the 8th week.

Without the presence of the olfactory neurons the olfactory bulb is incomplete and sense of smell is either diminished or absent totally. This absence can sometimes be detected by the use of MRI scans.

KAL-2, also known as fibroblast growth factor receptor 1(FGFR1) is thought to interact with anosmin-1 to allow the migration and final activation of the GnRH neurones and the olfactory neurones.

In most cases of HH and Kallmann's the GnRH producing cells are present and still functional but are unable to produce any affect because they are not attached to the hypothalamus.

Any functional defects with the hypothalamus and pituitary glands are normally ruled out before a diagnosis of HH or Kallmann's can be made.

DAX-1 is thought to produce a type of steroid receptor that works in conjunction with streroidgenic factor-1 (SF-1). It is thought amongst other functions the DAX-1 gene has a role in sexual differentiation. Mutations in the DAX-1 gene are also thought to be responsible to defects in sperm production as well. If DAX-1 occurs too often as in gene replication mutations it is thought to lead to male pseudo-hermaphroditism.