Kallmann syndrome

カルマン症候群

WordNet

1. a pattern of symptoms indicative of some disease
2. a complex of concurrent things; "every word has a syndrome of meanings"

PrepTutorEJDIC

1. (疾患の徴候となる一群の)症徴候,症候群 / (事件・社会的状態などのパターンを示す)徴候形態

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/05/19 12:57:12」(JST)

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Kallmann 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 condition which results in the failure to commence or the non-completion of puberty. It is characterised by hypogonadism and by a total lack of sense of smell (anosmia) or a heavily reduced sense of smell (hyposmia). The term hypogonadism describes a low level of circulating sex related hormones; (testosterone in men and oestrogen and progesterone in women).

It is part of a family of conditions that come under the term hypogonadotropic hypogonadism (HH). The condition can also be known as congenital hypogonadotrophic hypogonadism (CHH), isolated hypogonadotropic hypogonadism (IHH), hypothalamic hypogonadism or familial hypogonadism. The additional phrase "with anosmia" is used to indicate if a normal sense of smell is absent.

Kallmann syndrome is a specific form of isolated hypogonadotropic hypogonadism where there is an associated lack of sense of smell. Approximately 50% of HH cases occur with no sense of smell and are termed as Kallmann Syndrome. There is no distinction between Kallmann syndrome and other forms of HH in terms of diagnosis and treatment, apart from the fact that Kallmann syndrome is associated with the lack of sense of smell.

Abnormalities in various genes have be shown to disrupt the ability of the hypothalamus to produce gonadotrophin releasing hormone GnRH which in turn causes the pituitary to fail to release sufficient levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). LH and FSH have a direct action on the testes in men and ovaries in women.

The term hypogonadotropic hypogonadism (HH) reflects the disease mechanism. The term "hypo" means below or under. Hypogonadism means a low level of circulating sex hormones, testosterone for the men and oestrogen and progesterone for the women. Hypogonadotropic means low levels of the gonadotropin hormones, LH and FSH, normally secreted by the anterior pituitary gland under the influence of GnRH.

The term HH indicates a condition where there are low levels of testosterone or oestrogen and progesterone caused by low levels of FSH and LH. Overall Kallmann syndrome and other forms of HH cause a disruption in the communication pathway between the hypothalamus, pituitary and the testes or ovaries. The end result can be a failure to start or complete puberty, infertility and low levels of testosterone in men or oestrogen and progesterone in women.

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.

The condition has a low prevalence, estimated at 1 in 4,000 for male HH cases overall and 1:10,000 for Kallmann syndrome. It is three to five times more common in males than 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

The features of Kallmann Syndrome (KS) and hypogonadotropic hypogonadism (HH) can be split into two different categories; "reproductive" and "non reproductive". Not all symptoms will appear in every case of KS/HH, not even amongst family members. Some of these features are linked to the gene defects known to cause KS/HH but in some cases it is still not clear why some of these features exist. It has been estimated that 60% of KS/HH cases will show a non-reproductive symptom.

It is normally difficult to distinguish a case of KS/HH from a straightforward constitutional delay of puberty. However if a boy or girl has not started puberty by either 14 (girls) or 15 (boys) and they have one of the non-reproductive features then a referral to reproductive endocrinologist might be advisable.

Reproductive features

• Failure to start or fully complete puberty in both men and women
• Lack of testicular development in men; size <3 ml
• Primary amenorrhoea or failure to start menstruation in women
• Poorly defined secondary sexual characteristics in both men and women.
• Infertility

Non-reproductive features

• Hypogonadotropic hypogonadism (a lack of the pituitary hormones luteinizing hormone and follicle-stimulating hormone)
• Congenital (present from birth)
• Total lack of sense of smell (anosmia) or markedly reduced sense of smell (hyposmia). This is the defining feature of Kallmann syndrome; it is not seen in other cases of HH. Approximately 50% of HH cases occur with anosmia and can be termed as Kallmann syndrome.
• Cleft palate or other craniofacial defects.
• Unilateral renal agenesis or aplasia; absence or non-functioning of one of the kidneys
• Cryptorchidism; un-descended testicles at birth, occurs in 30% of KS/HH cases
• Micropenis, occurs in less than 5 to 10% of KS/HH cases
• Neural hearing defects
• Synkinesis or mirror movements of hands
• Dental defects
• Normally normal stature, but can have an increase in height if treatment is delayed due to the lack of testosterone or oestrogen causing excess bone growth in the arms and legs.

At one stage it was thought that colour blindness was linked to KS/HH but this has proved not to be the case.

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.

Patients with KS and other forms of HH are almost invariably born with normal sexual differentiation, i.e., they are physically male or female. This is due to the human chorionic gonadotropin (hCG) produced by placenta at approximately 12 to 20 weeks gestation (pregnancy) which is normally unaffected by having KS or HH.

Patients with KS/HH lack a surge of GnRH, LH and FSH that occurs between birth and six months of age. This surge is particularly important in infant boys as it helps with testicular descent into the scrotum. A small percentage of boys with KS/HH will be born with micropenis and/or undescended testes, both of which should be treated and corrected in the first year of life. The surge of GnRH/LH/FSH in non KS/HH children gives detectable levels of testosterone in boys and oestrogen & progesterone in girls. The lack of this surge can sometimes be used as a diagnostic tool if KS/HH is suspected in a newborn boy, but is not distinct enough for diagnosis in girls.

Diagnosis

The diagnosis is often one of exclusion found during the workup of delayed puberty.

A paper published in 2012 by Prof.Jacques Young highlights a typical example of the diagnositic work up involved in a suspected case of KS/HH.

One of the biggest problems in the diagnosis of Kallmann syndrome and other forms of HH is the ability to distinguish between a case of constitutional delay of puberty from a real case of Kallmann syndrome (KS) or hypogonadotropic hypogonadism (HH).

The main biochemical parameters in men are low serum testosterone and low levels of the gonadotropins LH and FSH, and in women low serum oestrogen and low levels of LH and FSH.

For both males and females, constitutional delay of puberty endogenous puberty will eventually commence without treatment. However a delay in treatment in a case of KS/HH will delay the physical development of the patient and can cause severe psychological damage. The "wait and see" approach of being a "late bloomer" is probably counterproductive to the needs of the patient whereas a step by step approach with hormone replacement therapy can be used as a diagnostic tool.

In females diagnosis is sometimes further delayed as other causes of amenorrhea normally have to be investigated first before a case of KS/HH is considered.

In males, treatment with age appropriate levels of testosterone can be used to distinguish between a case of KS/HH from a case of delayed puberty. If just delayed the testosterone can "kick-start" endogenous puberty proved by testicular enlargement. In a case of KS/HH there will be no testicular enlargement while on testosterone therapy alone. In the case of constitutional delay early treatment with age appropriate levels of testosterone will stimulate endogenous puberty. If no puberty is apparent, especially no testicular development than a review by a reproductive endocrinologist might be appropriate. Dr Richard Quinton, a leading UK expert on KS/HH suggests that if no puberty is not apparent by the age of 16 then the patient should be referred for endocrinological review.

A full endocrine work up will be required to measure the levels of the other pituitary hormones, especially prolactin to check the pituitary gland is working correctly. There can be other general health issues such as being overweight or having an underlying chronic or acute illness which could cause a delay of puberty. This makes it essential for a patient to get a full endocrine review to distinguish between a case of KS/HH or another cause for the pubertal delay.

Chronological bone age can be assessed using hand and wrist x-rays. If the chronological age is significant lower than the actual age of the patient, this could suggest delayed puberty unless there is another underlying reason for the discrepancy.

A karyotype may be performed to rule out Klinefelter syndrome and Turner syndrome although the hormones levels would also rule out both these relatively common reasons for hypogonadism.

A MRI test, (magnetic resonance imaging), can be used to examine for the presence of the olfactory bulb and to check for any physical irregularities with the pituitary gland or hypothalamus.

A standard smell test can be used to check for anosmia, but it must be remembered that even in total anosmia certain very caustic substatances such as bleach can still be detected by direct stimulation of the trigeminal nerve.

Genetic screening can be carried out, especially for the KAL-1 mutation, but in light of the uncertain genetic origin of the majority of KS and HH cases a negative result will not rule out a possible diagnosis.

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.

Diagram showing the normal migration of the GnRH releasing neurones from the olfactory placode into the hypothalamus. Also listed are the genes known to be involved in various steps in the process; mutations of which can lead to cases of KS or HH.

Prof. Nelly Pitteloud. 2011.

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.

Phenotypic spectrum of KS / HH cases

Kallmann syndrome and hypogonadotropic hypogonadism do not exist as distinct conditions. Each case can show a different range of symptoms and a different severity of symptoms. Even family members will not always show the same degree of symptoms. Cases of KS/HH can be separated into different categories depending on the gene mutation(s) involved. Severity can range from total absence of puberty with anosmia to slightly delayed puberty with or without anosmia.

Classic HH

This type of HH is present from birth and is lifelong. Approximately two thirds of cases will have a low level of pulsatile GnRH release from the hypothalamus which will give rise to partial puberty while the other third of cases will have zero GnRH release and no puberty.

The non-reproductive symptoms as mentioned earlier in this article will be present in approximately half the cases. The most common of which being anosmia, which gives rise to the distinction between KS and HH. Males with classic HH may also have had a history of un-descended testicles and / or micropenis.

This type of HH has been shown to be caused by polyallelic mutations in males and females and autosomal dominant and x-linked recessive mutations in males mentioned in the table earlier in this article.

Adult-onset HH

This type of HH has only been shown to occur in males. The hypothalamic-pituitary-gonadal axis (HPG axis) functions normally at birth and well into adult life giving normal puberty.

The HPG axis then fails, either totally or is reduced to a very low level of GnRH release, in adult life with no obvious cause such as a pituitary tumor. This will lead to a fall in testosterone levels and infertility. This type of HH is not associated with any non-reproductive symptoms. This type of HH has been shown to be caused by monoallelic mutations.

Reversible KS / HH

This type of KS / HH will appear to be the classic lifelong form at first but at some point in adult life the HPG axis resumes its normal function and GnRH, LH and FSH levels return to normal levels. Has only been shown to occur in 10% of cases, primarily KS cases rather than HH cases and only found in patients who have undergone some form of testosterone replacement therapy. It is only normally discovered when testicular volume increases while on testosterone treatment alone and testosterone levels return to normal when treatment is stopped.

This type of KS / HH rarely occurs in cases where males have had a history of un-descended testes and / or micropenis and has been shown to be caused by monoallelic mutations.

Hypothalamic amenorrhea

This type of HH is seen in females where the HPG axis is suppressed in response to physical or psychological stress or malnutrition. It is reversible with the removal of the stressor

This type of HH is not associated with any non-reproductive symptoms and has been shown to be caused by monoallelic mutations. A study suggested that there may have been an evolutionary advantage at one stage in the early development of man for these genes to exist where it could have been an advantage for the females not to be fertile at times when food was scarce in the community.

This type of HH has been shown to be caused by monoallelic mutations.

Normal puberty with non-reproductive symptom(s)

In this type of HH puberty occurs normally or is only slightly delayed and there might be a non-reproductive symptom, such as anosmia present. This type of HH has been shown to be caused by monoallelic mutations.

Treatment

Treatment for KS and other forms of HH can be split into two different categories:.

• Hormone replacement therapy
• Fertility treatments

Hormone replacement therapy

The aim for hormone replacement therapy (HRT) for both men and women is to ensure that the level of circulating hormones (testosterone for men and oestrogen/progesterone for women) is at the correct physiological level for the age of the patient. At first the treatment will produce most of the physical and psychological changes seen at puberty, with the major exception that there will be no testicular development in men and no ovulation in women.

After the optimum physical development has been reached HRT for men will continue to ensure that the normal androgen function is maintained; such as libido, muscle development, energy levels, hair growth and sexual function. In women, a variety of types of HRT will either give a menstruation cycle or not as preferred by the patient. HRT is very important in both men and women to maintain bone density and to reduce the risk of early onset osteoporosis.

The fertility treatments used for both men and women would still include hormone replacement in their action.

There are range of different preparations available for HRT for both men and women, a lot of these, especially those for women are the same used for standard HRT protocols used when hormone levels fall in later life or after the menopause.

For the men testosterone replacement is achieved either by using daily capsules, daily gel or patches, fortnightly injections, three monthly injections or six monthly implants. Tablet/capsule forms of HRT rarely give sufficient testosterone levels suitable for men with KS/HH.

The three monthly injection of testosterone undecanoate has become very popular over the past ten years. First produced by the Bayer pharmaceutical company and marketed under the names Nebido, Reandron or Aveed. It is still not available in the USA as it has yet to achieve a licence from the U.S. Food and Drug Administration (FDA).

After the first two injections which are six weeks apart; injections are taken every three months and give good testosterone levels throughout the three-month period with no noticeable tail off of levels at the end of the injection cycle. Some patients only require the injection every six months.

Some treatments may work better with some patients than others so it might be a case of personal choice as which one to use.

There are no specialist HRT treatments available just for women with KS/HH but there are multitude of different HRT products on the market including oral contraceptives and standard post-menopause products. Pills are popular but patches are also available. It may take some trial and error to find the appropriate HRT for the patient depending on how her body reacts to the particular HRT. Specialist medical advice will be required to ensure the correct levels of oestrogen and progesterone are maintained each month, depending on whether the patient requires continuous HRT (no-bleed) or a withdrawal option to create a "menstrual" type bleed.

Fertility treatments

Fertility treatments for people with KS/HH will require specialist advice from doctors experienced in reproductive endocrinology. There is a good success rate for achieving fertility for patients with KS/HH, with some experts quoting up to a 70% success rate, if IVF techniques are used as well. However there are factors that can have a negative effect on fertility and specialist advice will be required to determine if these treatments are likely to be successful.

Fertility treatments involve the administration of the gonadotropins LH and FSH in order to stimulate the production and release of eggs and sperm. Women with KS or HH have an advantage over the men as their ovaries normally contain a normal number of eggs and it sometimes only takes a couple of weeks of treatment to achieve fertility while it can take males up to two years of treatment to achieve fertility.

Human chorionic gonadotrophin (hCG) is sometimes used to stimulate testosterone production in men and ovulation induction in women. For men it acts in the same way as LH; stimulating the Leydig cells in the testes to produce testosterone. Common trade names for hCG products include; Pregnyl, Follutein, Profasi or Choragon. Some men with KS or HH take hCG solely for testosterone production.

Human menopausal gonadotrophin (hMG) is used in to stimulate sperm production in men and for multiple egg production and ovulation induction in women. It contains a mixture of both LH and FSH. In men the FSH acts on the sperm producing Sertoli cells in the testes. This can lead to testicular enlargement but can take anything from 6 months to 2 years for an adequate level of sperm production to be achieved. Common trade names for hMG products include; Menopur, Menogon, Repronex or Pergonal.

Purified forms of FSH are also available and are sometimes used in conjunction with hCG instead of using hMG.

Injections can be intramuscular but are normally taken just underneath the skin (subcutaneous) and are normally taken two or three times a week.

For both men and women, an alternative method (but not widely available), is the use of an infusion pump to provide GnRH (or LHRH) in pulsatile doses throughout the day. This stimulates the pituitary gland to release natural LH and FSH in order to activate testes or ovaries.

Osteoporosis

One possible side effect of having KS/HH is the increased risk of developing secondary osteoporosis or osteopenia. Oestrogen (females) and testosterone (males) is essential for maintaining bone density. Deficiency in either testosterone or oestrogen can increase the rate of bone resorption while at the same time slowing down the rate of bone formation. Overall this can lead to weakened, fragile bones which have a higher tendency to fracture.

Even a short time with low oestrogen or testosterone, as in cases of delayed diagnosis of KS/HH can lead to an increased risk of developing osteoporosis but other risk factors are involved so the risk of developing it will vary from patient to patient.

Patients with KSéHH should have a bone density scan at least every five years, even if they are on constant hormone replacement therapy. This interval will be shortened to three years if the patient is already in the at-risk zone (osteopenia) or yearly if the patient has osteoporosis already.

The bone density scan is known as a Dual energy X-ray absorptiometry scan (DEXA or DXA scan). It is a very simple straightforward test, taking less than 15 minutes to perform and involves taking a specialised x-ray picture of the spine and hips and measuring the bone mineral density and comparing the value to the average value of a young healthy adult in the general population.

Adequate calcium levels, and probably more importantly Vitamin D levels are essential for healthy bone density. Some patients with KS/HH will have their levels checked and may be prescribed extra Vitamin D tablets or injections to try to prevent the condition getting worse. The role of Vitamin D for general overall health is under close scrutiny at the moment with some researchers claiming Vitamin D deficiency is prevalent in many populations and can be linked to other disease states.

Some people with severe osteoporosis might be prescribed biphosphonates. Exercise, especially weight bearing and resistance exercise, is known to reduce the risk of osteoporosis.

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.

Epidemiology

The prevalence of idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS) has been estimated to be in the region of 1 in 10,000 male births. This figure comes from a 1973 study of French Foreign Legion conscripts

Since there is no genetic consensus for the diagnosis of KS and IHH it does make finding a reliable figure for the incidence difficult. There is a certain amount of confidence in the figure quoted in the 1973 study as the figure quoted for Klinefelter syndrome closely matches the currently accepted rate.

It is believed to be five times more common in males than females but there is no obvious genetic reason for this, even though two of the associated gene defects occur on the x-chromosome.

KS and IHH show all versions of genetic inheritance; both x linked or autosomal and dominant or recessive inheritance. Mutations in the KAL-1 gene on the x-chromosome can cause x-linked KS in isolation but other cases of KS and IHH show probable digenic properties, with two gene defects working in combination.

While KS and IHH are normally considered to be congenital conditions other forms have been reported including adult onset IHH and potentially reversible IHH. Cases within the same family do not show the same range symptoms perhaps highlighting the diverse genetic nature of the conditions.

There may also be no obvious family history of inheritance (sporadic or isolated cases), but any case of KS or IHH does have the potential to be passed on to future generations.

Unless there are no accompanying conditions such as heart or neural defects there is normally no effect on life expectancy.

Early onset osteoporosis due to low levels of testosterone or oestrogen can cause problems but otherwise KS and IHH if treated correctly are not associated with a high level of morbidity.

European Consortium

In 2011 a team led by Prof. Nelly Pitteloud and Andrew Dwyer of the University Hospital of Lausanne (CHUV) in Switzerland proposed the formation of a European wide research consortium funded by the European Cooperation on Science and Technology organisation (COST) that would provide a framework for clinicians and researchers to collaborate their research into GnRH deficiency conditions, including Kallmann syndrome and other forms of hypogonadotropic hypogonadism. The first meeting of COST Action BM1105[1] was held in Brussels in February 2013. The website (www.gnrhnetwork.eu) of the consortium was launched in March 2013 and will contain information for patients with GnRH deficient conditions and in time clinical guidelines for the diagnosis and treatment of such conditions.

See also

• Isolated hypogonadotropic hypogonadism
• Hypogonadotropic hypogonadism
• Hypogonadism
• Delayed puberty
• Infertility
• Gonadotropin-releasing hormone insensitivity
• Anosmia

References

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)

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• 1. 先天性性腺刺激ホルモン放出ホルモン欠乏症（特発性低ゴナドトロピン性性腺機能低下） congenital gonadotropin releasing hormone deficiency idiopathic hypogonadotropic hypogonadism
• 2. 男性における続発性性腺機能低下の原因 causes of secondary hypogonadism in males
• 3. 性腺機能低下を呈する男性の臨床的特徴および診断 clinical features and diagnosis of male hypogonadism
• 4. 思春期遅発症の診断および治療 diagnosis and treatment of delayed puberty
• 5. 味覚および嗅覚障害の解剖学および病因 anatomy and etiology of taste and smell disorders

English Journal

• Reproductive dysfunction and decreased GnRH neurogenesis in a mouse model of CHARGE syndrome.

• Layman WS, Hurd EA, Martin DM.AbstractCHARGE is a multiple congenital anomaly disorder and a common cause of pubertal defects, olfactory dysfunction, growth delays, deaf-blindness, balance disorders and congenital heart malformations. Mutations in CHD7, the gene encoding chromodomain helicase DNA binding protein 7, are present in 60-80% of individuals with the CHARGE syndrome. Mutations in CHD7 have also been reported in the Kallmann syndrome (olfactory dysfunction, delayed puberty and hypogonadotropic hypogonadism). CHD7 is a positive regulator of neural stem cell proliferation and olfactory sensory neuron formation in the olfactory epithelium, suggesting that the loss of CHD7 might also disrupt development of other neural populations. Here we report that female Chd7(Gt/+) mice have delays in vaginal opening and estrus onset, and erratic estrus cycles. Chd7(Gt/+) mice also have decreased circulating levels of luteinizing hormone and follicle-stimulating hormone but apparently normal responsiveness to gonadotropin-releasing hormone (GnRH) agonist and antagonist treatment. GnRH neurons in the adult Chd7(Gt/+) hypothalamus and embryonic nasal region are diminished, and there is decreased cellular proliferation in the embryonic olfactory placode. Expression levels of GnRH1 and Otx2 in the hypothalamus and GnRHR in the pituitary are significantly reduced in adult Chd7(Gt/+) mice. Additionally, Chd7 mutant embryos have CHD7 dosage-dependent reductions in expression levels of Fgfr1, Bmp4 and Otx2 in the olfactory placode. Together, these data suggest that CHD7 has critical roles in the development and maintenance of GnRH neurons for regulating puberty and reproduction.
• Human molecular genetics.Hum Mol Genet.2011 Aug 15;20(16):3138-50. Epub 2011 May 19.
• CHARGE is a multiple congenital anomaly disorder and a common cause of pubertal defects, olfactory dysfunction, growth delays, deaf-blindness, balance disorders and congenital heart malformations. Mutations in CHD7, the gene encoding chromodomain helicase DNA binding protein 7, are present in 60-80%
• PMID 21596839

Japanese Journal

• Keratinocyte-derived anosmin-1, an extracellular glycoprotein encoded by the X-linked Kallmann syndrome gene, is involved in modulation of epidermal nerve density in atopic dermatitis

• TENGARA Suhandy,TOMINAGA Mitsutoshi,KAMO Atsuko,TANEDA Kenichi,NEGI Osamu,OGAWA Hideoki,TAKAMORI Kenji
• Journal of dermatological science 58(1), 64-71, 2010-04-01
• NAID 10027400427

Related Links

• Kallmann syndrome - Wikipedia, the free encyclopedia

Kallmann syndrome is a genetic disorder marked by anosmia 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 ...

Related Pictures

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★リンクテーブル★

リンク元	「カルマン症候群」
関連記事	「syndrome」

「カルマン症候群」

　　[★]

英

Kallmann's syndrome Kallmann syndrome

同

Kallmann症候群

概念

• 視床下部の神経核の発生異常により無嗅覚症/低嗅覚症を合併する低ゴナドトロピン性性腺機能低下症

遺伝

• X連鎖劣性遺伝、常染色体劣性遺伝、常染色体優性遺伝

病態

• 視床下部の先天性の形成異常(神経核の欠損など)を来して、GnRHの分泌低下と嗅覚の異常を呈する。

症候

• 嗅覚異常
• 男性：類宦官症、女性化乳房
• 女性：原発性無月経

検査

• FSH、LH低値

鑑別疾患

• GnRH単独欠損症
• GnRH受容体異常症

治療

• 挙児を希望する場合にはhCG-hMG療法やGnRHの間欠投与

参考

• 1. [charged] 先天性性腺刺激ホルモン放出ホルモン欠乏症（特発性低ゴナドトロピン性性腺機能低下） - uptodate [1]

OMIM

• 1: #308700. KALLMANN SYNDROME 1; KAL1; Gene map locus Xp22.3

http://omim.org/entry/308700

• 2: #147950. KALLMANN SYNDROME 2; KAL2; Gene map locus 8p11.2-p11.1

http://omim.org/entry/147950

• 3: #244200. KALLMANN SYNDROME 3; KAL3; Gene map locus 20p13

http://omim.org/entry/244200

• 4: #610628. KALLMANN SYNDROME 4; KAL4; Gene map locus 3p21.1

http://omim.org/entry/610628

• 5: #612370. KALLMANN SYNDROME 5; KAL5; Gene map locus 8q12.1

http://omim.org/entry/612370

• 6: #612702. KALLMANN SYNDROME 6; KAL6; Gene map locus 10q24

http://omim.org/entry/612702

国試

• 104D037、087B079

「syndrome」

　　[★]

• n.

• 症候群