Kallmann syndrome

Kallman syndrome
Classification and external resources
The structure of GNRH1 (from PDB 1YY1)
ICD-10	E23.0
ICD-9	253.4
OMIM	308700 147950 244200 138850 607002
DiseasesDB	7091
eMedicine	med/1216 med/1342
MeSH	D017436

Kallmann syndrome is a genetic disorder marked by anosmia (inability to perceive odors) and hypogonadism (the decreased functioning of the glands that produce sex hormones). Abnormalities in various genes may cause a defect in the hypothalamus, causing a deficiency of gonadotropin-releasing hormone (GnRH); this in turn causes deficiences in FSH and LH levels. Kallmann syndrome is also called hypothalamic hypogonadism, familial hypogonadism with anosmia, and hypogonadotropic hypogonadism, reflecting its disease mechanism.

Kallmann syndrome was described in 1944 by Franz Josef Kallmann, a German-American geneticist. However, others, such as the Spanish doctor Aureliano Maestre de San Juan in 1856, had noticed a correlation between anosmia and hypogonadism.^{[citation needed]} The condition has a low prevalence, and is estimated at 1:10,000 males and 1:50,000 females.

The best-known person who has Kallmann syndrome is the jazz vocalist Jimmy Scott. In 2004, Canadian writer Brian Brett published a memoir, Uproar's Your Only Music, about growing up with Kallmann syndrome.

Features

Kallmann syndrome's characteristics:

• Hypogonadotropic hypogonadism (a lack of the pituitary hormones LH and FSH)
• Congenital (present from birth) anosmia (complete inability to smell) or hyposmia (decreased ability to smell)
• Normal stature

It can occasionally be associated with optic problems, such as colour blindness or optic atrophy, nerve deafness, cleft palate, cryptorchidism, renal agenesis, and mirror movement disorder. However, it is not clear how, if at all, these other problems have the same cause as the hypogonadism and anosmia.

Males present with delayed puberty and may have micropenis (although congenital micropenis is not present in most male KS cases).

Females present with delayed puberty (i.e., primary amenorrhea) and lack of secondary sex characteristics, such as breast development.

A fraction of cases may present with post-pubertal onset, which results in a phenotypically normal penis in men with subsequent testicular atrophy and loss of some secondary sex traits. These men generally present with sexual impairment and low libido. In women, late-onset Kallmann Syndrome can result in secondary amenorrhea. Anosmia may or may not be present in these individuals.

Diagnosis

The diagnosis is often one of exclusion found during the workup of delayed puberty. The presence of anosmia with delayed puberty should suggest Kallmann syndrome.

Pathophysiology

Under normal conditions, GnRH travels from the hypothalamus to the pituitary gland via the hypophyseal portal system, where it triggers production and release of gonadotropins (LH and FSH) from the gonadotropes. When GnRH is low, the pituitary does not create the normal amount of gonadotropins. The gonadotropins normally increase the production of gonadal steroids; so, when they are low, these steroids will be low as well.

In Kallmann syndrome, the GnRH neurons do not migrate properly from the olfactory placode to the hypothalamus during development. The olfactory bulbs also fail to form or have hypoplasia, leading to anosmia or hyposmia.

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.

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.

Treatment

Treatment is directed at restoring the deficient hormones—hormone therapy (HT). Males are administered human chorionic gonadotropin (hCG) or testosterone. Females are treated with estrogen and progestins.

There are a range of different methods for the delivery of HRT, especially for men. The short acting monthly injection is now less widely used in favour of the longer lasting injection, Nebido, which can last from 3 to 6 months depending on the individual. Daily application gels and patches are also available as are implants inserted every 6 months.

Tablets are not thought to be effective for the treatment of Kallmann syndrome due to their low bio-availability once processed by the liver, though this can be overcome by using oil filled capsules which allows the testosterone to reach the blood stream in effective doses.

To induce fertility in males or females, GnRH (aka LHRH) is administered by an infusion pump, or hCG/hMG/FSH/LH combinations are administered through regular injections. Fertility is maintained only during treatment with these hormones. Once fertility treatment stops, it is necessary to revert to the normal hormone-repleacement therapy (HRT) of testosterone for men and estrogen and progestins for women.

The main health risk, for both men and women, of untreated Kallmann Syndrome is osteoporosis. Therefore, regular bone-density scans (every two years or so) are advisable, even if with HRT. Additional medication specifically for osteoporosis is necessary in some cases.

Epidemiology

Kallmann syndrome occurs at a rate of 1 in 10,000 male births and 1 in 50,000 female births. It may be inherited as an X-linked condition, an autosomal dominant condition, or as an autosomal recessive condition. Statistics are sparse, but it seems that autosomal dominant is the most common form of heredity.

One recent paper estimated its incidence at 0.025%, or 1 in 4,000, with the female incidence being 3 to 5 times less.

Even though mutations in the KAL-1 gene on the X chromosome can cause Kallmann syndrome, only 11–14% of patients with Kallmann syndrome have detectable KAL-1 mutations.

Autosomal dominant mutations have been described with the FGFR-1 (8p12) gene, sometimes called the KAL-2 gene. This is thought to cause about 10% of cases. However, about 70% of KS cases seem to be the result of autosomal dominant genes, though the identity of those genes is not yet known.

Autosomal recessive mutations of the GnRH-receptor gene (4q13.2) have also been reported. This defect appears to produce a wider spectrum of physical symptoms than with the other gene defects, and the defect lies in the ability of the pituitary gland to recognize GnRH, rather than the ability of the hypothalamus to produce GnRH. There is debate about whether this is in fact Kallmann Syndrome, because the GnRH-receptor development is not related to anosmia.

There may also be no obvious family history of inheritance (sporadic cases). However, it is possible for Kallmann Syndrome genes to be passed on to children of a sporadic case.

Psychology

In some cases, the psychological effects of having this condition can outweigh the significance of any physical symptoms.

The social stigma of being left behind by the peer group at a vital stage of physical and emotional development can cause lasting damage in some patients. Some with Kallmann Syndrome find it difficult to fit in to social groups and may have trouble forming relationships, both physically and emotionally. This might be more profound in people who receive diagnoses later in life. There appear to be a range of psychological outcomes for people with KS from relatively mild to chronic in which the whole 'self' is shaped by having the syndrome. In these people their self-image is essentially filtered through the fact that they have KS. Feelings of inadequacy, being worth less than others and anxiety states may result in some patients. The condition appears to affect men psychologically to a greater degree than women, on average.

Practical Issues

While the lack of sense of smell may not be important when compared to the lack of sexual development, it does give rise to some situations in which care should be taken.

Personal hygiene can be a major issue for people without a sense of smell in any social situation. People with Kallmann syndrome may not be aware of the impression they give to other people in close contact with them in terms of odours, either from themselves or their clothes.

Gas leaks within the home can be a serious problem and fitting gas detectors within the home is recommended.

Extra care should be taken with spoilage of food and drink, extra care should be taken with the expiration dates.

A patient’s perspective

Having Kallmann syndrome can have a profound effect on a person’s life, however it will affect different people in different ways. Age of diagnosis and treatment is a big key to how well an individual patient copes with the condition. For some patients the ability to put a name to the condition and the knowledge that they are not the only person in the world with this condition is very reassuring.

With the key symptom being not going through puberty at the normal age it can produce a huge effect on a person’s social development as well as physical development.

It will vary from person to person but in general men with Kallmann syndrome will have a smaller penile length than the average for the population, which in addition to the lack of testicular development can affect self confidence to such a degree that sexual activity is not even attempted. Most men with Kallmann syndrome can have a normal, active sex life but the confidence required to achieve this is sometimes beyond some men with Kallmann syndrome and they have less sexual activity than other people the same age.

Another aspect of Kallmann syndrome is the social isolation. Since it is such a rare condition a lot of patients with Kallmann syndrome have never even met or talked to a fellow patient. The ability to meet and talk to other people with the condition goes a long way to helping a patient come to terms with the condition.

The treatment of patients with Kallmann syndrome is fairly straightforward once diagnosed with the use of hormone replacement therapies and fertility injections in some cases. The bigger issue is the initial diagnosis, especially in the crucial teenage years. The patients that cope better with Kallmann syndrome on the whole are those that are diagnosed before the age of 16 and have prompt treatment. Problems can arise if people are told to “wait and see” too long into their teenage years instead of being referred for specialist endocrinologist review where a case of pubertal delay can be separated from a case of Kallmann syndrome.

Outwardly there is nothing striking about a person with Kallmann syndrome. They will not look any different from anybody else, and come in all different shapes and sizes. Once treatment is started and normal hormone levels are restored there are no side effects or life expectancy issues associated with having Kallmann syndrome. The lack of sense of smell might be noticed by people, but this can easily be explained away without going into a full description of Kallmann syndrome.

External links

• GeneReviews/NCBI/NIH/UW entry on Kallmann syndrome
• Updated information web site on Kallmann syndrome
• Information web site on Kallmann's syndrome
• "Man, 33, seeks puberty", the case of Lawrence Koomson, a physician who was treated for the condition as filmed in the documentary. (BBC)