Kallmann syndrome

Kallmann syndrome
The structure of GNRH1
(from PDB: 1YY1​)
Classification and external resources
Specialty endocrinology
ICD-10 E23.0
ICD-9-CM 253.4
OMIM 308700 147950 244200 138850 607002 146110 136350 615271 615270 614880 1527600 162330 164160 608137 608892 300473 603286 613301 604808 603725 606807 602748607984
DiseasesDB 7091
eMedicine med/1216 med/1342
MeSH D017436

Kallmann syndrome is a rare genetic hormonal condition that is characterized by a failure to start or a failure to complete puberty. It is also accompanied by a lack of sense of smell (anosmia) or a highly reduced sense of smell (hyposmia). The condition can occur in both males and females but is more commonly diagnosed in males. Left untreated, patients with Kallmann syndrome will almost invariably be infertile.

Kallmann syndrome is a form of hypogonadotropic hypogonadism (HH). Approximately 50% of HH cases occur with no sense of smell and are classified as Kallmann syndrome. Apart from the sense of smell there is no difference in the diagnosis or treatment between a case of HH or a case of Kallmann syndrome.[1][2]

The terminology used when describing cases of HH can vary, other terms used to describe the condition include:

The term isolated GnRH deficiency (IGD) has increasingly been used to describe this group of conditions as it highlights the primary cause of these conditions and distinguishes them from other conditions such as Klinefelter syndrome or Turner syndrome which share some similar symptoms but have a totally different etiology.[4]

The term hypogonadism describes a low level of circulating sex hormones; testosterone in males and oestrogen and progesterone in females. Hypogonadism can occur through a number of different mechanisms. The use of the term hypogonadotropic relates to the fact that the hypogonadism found in HH is caused by a disruption in the production of the gonadotropin hormones normally released by the anterior pituitary gland known as luteinising hormone (LH) and follicle stimulating hormone (FSH).

LH and FSH have a direct action on the ovaries in women and testes in men. The absence of LH and FSH means that initially puberty will not commence at the correct time, and subsequently the ovaries and testes will not perform their normal fertility function with the maturation and release of eggs in women and the production of sperm in men alongside their role in producing the sex hormones.

The underlying cause of the failure in production of LH and FSH is the impairment of the hypothalamus to release the hormone GnRH which in normal circumstances induces the production of LH and FSH. Without the correct release of GnRH the pituitary gland is unable to release LH and FSH which in turn prevents the ovaries and testes from functioning correctly. This failure in GnRH production can either be due to the absence of the GnRH releasing neurones inside the hypothalamus [5] or the inability of the hypothalamus to release GnRH in the correct pulsatile manner to ensure LH and FSH release from the pituitary.[6]

HH can occur as an isolated condition with just the LH and FSH production being affected or it can occur in combined pituitary deficiency conditions such as in CHARGE syndrome.

Kallmann syndrome was described in a paper published in 1944 by Franz Josef Kallmann, a German-American geneticist.[7][8] The link between anosmia and hypogonadism had already been noted however, in particular by the Spanish doctor Aureliano Maestre de San Juan in 1856.[9] The condition is sometimes known by his name in Spanish speaking countries.

The CHH condition has a low prevalence, estimated as being between 1 in 4,000 and 1 in 10,000 for male HH cases overall, of which about a half are Kallmann syndrome (KS) cases. It is three to five times more common in males than females. Though whether this is a true sex imbalance or a reflection on how difficult KS / HH is to diagnose correctly, especially in females, has yet to be fully established.[10][11] A more recent paper published in 2011[12] gave the incidence in the Finnish population at 1 in 48,000, with a sex distinction of 1 in 30,000 for males and 1 in 125,000 for females.

Signs and symptoms

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

It is normally difficult to distinguish a case of KS/CHH from a straightforward constitutional delay of puberty. However, if puberty has not commenced by either 14 (girls) or 15 (boys) and one of these non-reproductive features are present then a referral to reproductive endocrinologist might be advisable.

Each KS/CHH case can show a different range of symptoms and a different severity of symptoms. Severity can range from total absence of puberty with anosmia to slightly delayed puberty with or without anosmia. Even family members will not always show the same degree of symptoms. In the same family with the same KS gene defect, some members may have complete KS with no sense of smell, others may have CHH with some sense of smell, and still others may have isolated anosmia and no hormone deficiencies.[6] Cases of KS/CHH can be separated into different categories depending on the gene mutation(s) involved.[13]

Classic CHH

This type of HH is present from birth and is lifelong. Approximately two-thirds of classic CHH 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 mentioned earlier in this article will be present in approximately half the cases. The most common of these is anosmia, which gives rise to the distinction between KS and normosmic CHH. Males with classic CHH may also have had a history of un-descended testicles and/or micropenis.

This type of CHH has been shown to be caused by autosomal recessive or dominant mutations in males and females, and X chromosome-linked recessive mutations in males mentioned in the table at the end of 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 either fails 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, and it has been shown to be caused by monoallelic mutations.

Reversible KS/HH[14][15]

This type of KS/CHH 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 normosmic CHH cases rather than KS 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/CHH 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 amenorrhoea[16]

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 mutations 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.

Reproductive features

Non-reproductive features[1][17]

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 HH can result in secondary amenorrhoea. Anosmia may or may not be present in these individuals.

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

Patients with KS/CHH lack a surge of GnRH, LH, and FSH that occurs between birth and six months of age.[20] This surge is particularly important in infant boys as it helps with testicular descent into the scrotum. A small percentage of boys with KS/CHH will be born with micropenis (fewer than 5 to 10% of cases) and/or cryptorchidism (undescended testes; 30% of cases), which may be treated surgically in the first year of life. The surge of GnRH/LH/FSH in non KS/CHH 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/CHH is suspected in a newborn boy, but is not distinct enough for diagnosis in girls.

Osteoporosis

One possible side effect of having KS/CHH is the increased risk of developing secondary osteoporosis or osteopenia. Oestrogen (females) or testosterone (males) is essential for maintaining bone density.[2] 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/CHH 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 KS/CHH 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. It involves taking a specialised X-ray picture of the spine and hips and measuring the bone mineral density and comparing the result to the average value for a young healthy adult in the general population.[21]

Adequate calcium levels, and probably more importantly vitamin D levels are essential for healthy bone density. Some patients with KS/CHH 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 bisphosphonates. Exercise, especially weight bearing and resistance exercise, is known to reduce the risk of osteoporosis.

Reversal of symptoms

Reversal of symptoms have been reported in between 15% to 22% of cases.[22] The causes of this reversal are still under investigation but have been reported in both males and females.

Reversal appears to be associated with 14 of the known gene defects linked to KS/CHH. The study suggests no obvious gene defect showing a tendency to allow reversal. There is a suggestion that the TAC3 and TACR3 mutations might allow for a slightly higher chance of reversal, but the numbers involved are too low to confirm this. The ANOS1 mutations appear to be least likely to allow reversal with to date only one recorded instance in medical literature. Even male patients who previous had micro-phallus or cryptorchidism have been shown to undergo reversal of symptoms.

The reversal might not be permanent and remission can occur at any stage; the paper suggests that this could be linked to stress levels. The paper highlighted a reversal case that went into remission but subsequently achieved reversal again, strongly suggesting an environmental link.

Reversal cases have been seen in cases of both KS and normosmic CHH but appear to be less common in cases of KS (where the sense of smell is also affected). A paper published in 2016[23] agreed with the theory that there is a strong environmental or epigenetic link to the reversal cases. The precise mechanism of reversal is unclear and is an area of active research.

Reversal would be apparent if testicular development was seen in men while on testosterone therapy alone or in women who menstruate or achieved pregnancy while on no treatment. To date there have been no recorded cases of the reversal of anosmia found in Kallmann syndrome cases.

Diagnosis

The diagnosis is often one of exclusion found during the workup of delayed puberty.[10][24][25]

A paper published in 2012 by Prof. Jacques Young[26] highlights a typical example of the diagnostic work up involved in a suspected case of KS/CHH.

One of the biggest problems in the diagnosis of KS and other forms of CHH is the ability to distinguish between a normal constitutional delay of puberty and KS or CHH.[27]

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 with 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 applied to "late bloomers" is probably counterproductive to the needs of the patient whereas a step-by-step approach with hormone replacement therapy used with slowly increasing doses can be used as a diagnostic tool.

Normally testicular enlargement is the key sign for the onset of puberty in boys however the use of nighttime LH sampling can help predict the onset of puberty.

In females diagnosis is sometimes further delayed as other causes of amenorrhoea normally have to be investigated first before a case of KS/CHH is considered.[28] KS/CHH can still occur in females in cases when menstruation has begun but stopped after one or two menstrual bleeds. A study of GnRH deficient women in 2011[29] showed that 10% had experienced one or two bleeds before the onset of amenorrhoea.

In males, treatment with age-appropriate levels of testosterone can be used to distinguish between a case of KS/CHH from a case of delayed puberty. If just delayed the testosterone can "kick-start" endogenous puberty, as demonstrated by testicular enlargement, whereas in the case of KS/CHH there will be no testicular enlargement while on testosterone therapy alone. If no puberty is apparent, especially no testicular development, then a review by a reproductive endocrinologist may be appropriate. Dr Richard Quinton, a leading UK expert on KS/CHH, suggests that if puberty is not apparent by the age of 16 then the patient should be referred for endocrinological review.[30]

A full endocrine workup will be required to measure the levels of the other pituitary hormones, especially prolactin, to check that 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/CHH and another cause for the pubertal delay.

Bone age can be assessed using hand and wrist X-rays. If the bone age is significantly lower than the chronological 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 magnetic resonance imaging (MRI) scan can be used to determine whether the olfactory bulb is present and to check for any physical irregularities of 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 various substances (such as menthol and alcohol) can still be detected by direct stimulation of the trigeminal nerve.

Genetic screening can be carried out, but in light of the unknown genes involved in the majority of KS and CHH cases, a negative result will not rule out a possible diagnosis.

A review paper published in 2014[31] highlighted the need for doctors to be aware of the possible diagnosis of KS / HH if pubertal delay is found alongside associated "red flag" symptoms. The symptoms listed in the paper were split into two categories; reproductive symptoms associated with the lack of mini puberty seen between birth and six months of age and non-reproductive symptoms which are associated with specific forms of HH. As with other review papers the authors also warned against the "wait and see" approach when puberty appears to be delayed.

Pathophysiology

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 to 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.
The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism

Kallmann syndrome (KS) and other forms of hypogonadotropic hypogonadism (HH) are classed as pituitary or endocrine disorders. While the end result is a failure of puberty and the development of secondary sexual characteristics, the underlying cause of the disorder is located between the 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. These glands secrete a number of different hormones with various 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.

Normally the hypothalamus releases a hormone called gonadotropin releasing hormone (GnRH). GnRH is released by specialised nerve cells or neurones of the hypothalamus into the hypophyseal portal system in a pulsatile manner at set intervals throughout the day, and acts on the anterior pituitary gland, causing it to release two hormones called gonadotropins. These hormones are luteinising hormone (LH) and follicle stimulating hormone (FSH), which have a direct action on the testes in men and ovaries in women. LH and FSH are essential for stimulating the development of secondary sexual characteristics seen at puberty and for 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. In KS/CHH the release of GnRH is either absent or markedly reduced.

In the first 10 weeks of normal embryonic development the GnRH releasing neurones migrate from their original source in the nasal region and end up inside the hypothalamus. These neurones originate in an area of the developing head, called the olfactory placode, that will give rise to the nose; they then pass through the cribriform plate, along with the fibres of the olfactory nerves, and into the rostral forebrain. From there they migrate to what will become the hypothalamus. Any problems with the development of the olfactory nerve fibres will prevent the progression of the GnRH releasing neurones towards the brain.[32] 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 deficient production of testosterone in men, and oestrogen and progesterone in women. In KS the olfactory nerve fibres are interrupted in the frontonasal region, and the olfactory bulbs are missing or not fully developed, which gives rise to the additional symptom of lack of sense of smell (anosmia) or strongly reduced sense of smell (hyposmia). In other forms of CHH the olfactory nerves and olfactory bulbs develop correctly, so there is a normal sense of smell and the migration of the GnRH releasing neurones is not affected, but some hypothalamic defect prevents GnRH from being released, or alternatively, the hormone is released but cannot stimulate the cells of the pituitary gland because the hormone receptor is absent or not functional. The genes that have been implicated in KS or CHH play a part in the generation, migration, or activity of these GnRH releasing neurones, or in the ability of GnRH to stimulate FSH and LH production.

Treatment

Treatment for KS and other forms of HH can be divided into hormone replacement therapy and fertility treatments.[20][24][25][33]

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 normal 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 is a 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. Different formulations of testosterone are available for treatment which will contain single or multiple forms of testosterone.[31]

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. In early 2014 Aveed was licensed for use in the US by the Food and Drug Administration (FDA), produced in 3ml vials as opposed the regular 4ml vials used elsewhere around the world.

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 tailing-off of levels at the end of the injection cycle. Some patients only require the injection every six months. These injection intervals might be adjusted depending on the response of the individual.

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. This withdrawal bleed can be monthly or over longer time periods depending on the type of medication used.

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 few months of treatment to achieve fertility while it can take males up to two years of treatment to achieve fertility.

A new potential new form of fertility treatment underwent clinical trials in 2013 and 2014 by Merck Sharp & Dohme. The trial evaluated a longer acting form of FSH, in the form of corifollitropin alfa. Injections were taken fortnightly instead of the normal twice weekly it is hoped that this would induce sperm production within months rather than the two years it can take with currently available medications.[34]

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 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 with hCG instead of using hMG.

Females with KS / HH would normally require both hCG and FSH in order to achieve fertility. Other cases of female infertility can be treated with just FSH but females (and most males) with KS / CHH would require the use of both forms of gonadotropin injection.

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. The use of Kisspeptin delivered in the same pulsatile manner is also under evaluation as a possible treatment for fertility induction.

Genetics and inheritance

To date at least twenty five different genes have been implicated in causing Kallmann syndrome or other forms of HH through a disruption in the production or activity of GnRH. These genes involved cover all forms of inheritance and no one gene defect has been shown to be common to all cases which makes genetic testing and inheritance prediction difficult.[35]

Some of the genes known to be involved in cases of KS / CHH are listed in the Online Mendelian Inheritance in Man ((OMIM)) table at the end of this article.

A 2007 paper proposed a possible digenic model for Kallmann syndrome and other forms of hypogonadotrophic hypogonadism.[13] The possibility of two separate gene defects working in combination could account for some of the variation of symptoms seen in cases of Kallmann syndrome, even within families.

The genetics of Kallmann syndrome and other forms of hypogonadotrophic hypogonadism is still far from clear with more than 50% of cases having an unknown genetic origin.[36]

Further research published by Anna Mitchell et al.[6] has highlighted the fact that the number of genetic loci known to cause cases of Kallmann syndrome and CHH is still increasing. The paper highlights the broad spectrum of physical symptoms—both reproductive and non-reproductive—that can occur in cases of Kallmann syndrome, even within the same family group.

Epidemiology

The prevalence of congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) has been estimated to be in the region of 1 in 10,000 male births.[37] This figure comes from a 1973 study of French Foreign Legion conscripts[11] A more recent paper published in 2011[12] gave the incidence in the Finnish population at 1 in 48,000, with a sex distinction of 1 in 30,000 for males and 1 in 125,000 for females.

Since there is no genetic consensus for the diagnosis of KS and CHH, and mild clinical forms can be overlooked, it does make finding a reliable figure for the prevalence of the disease difficult. It is believed to be between four and five times more common in males than females, but there is so far no obvious genetic reason for this, even though two of the associated gene defects occur on the X-chromosome.

KS and CHH show all versions of genetic inheritance; both X-linked and autosomal dominant or recessive inheritance. Mutations in the ANOS1 gene on the X-chromosome can cause X-linked KS in isolation, but other cases of KS and CHH show probable digenic or oligogenic transmission of the disease, with two (or more) gene defects working in combination.

While KS and CHH are considered to be congenital conditions, other forms have been reported including adult onset IHH and potentially reversible IHH. Cases within the same family often do not show the same range of 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 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.

Society and culture

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 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 clinicians, researchers and patients with GnRH deficient conditions. In 2015 the clinical working group published a consensus paper on the diagnosis and treatment of patients with Kallmann syndrome and other forms of GnRH deficiency.[1]

Notable cases

The best-known person who had Kallmann syndrome was probably the jazz vocalist Jimmy Scott; the syndrome was a contributing factor to Scott's unusually high-pitched and distinctive singing voice. In 2004, Canadian writer Brian Brett published a memoir, Uproar's Your Only Music, about growing up with Kallmann syndrome.[38]

Patient 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.[39] 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. In addition, the impact of an impaired sense of smell on everyday life (flavor of food, detection of bad odors,...) should not be underestimated, and both men and women affected by Kallmann syndrome often complain about it.

Another aspect of Kallmann syndrome is 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.[40]

Research

Kisspeptin is a protein that regulates the release of GnRH from the hypothalamus, which in turn regulates the release of LH and to a lesser extent, FSH from the anterior pituitary gland. Kisspeptin and its associated receptor KISS1R are known to be involved in the regulation of puberty.

Studies have shown there is potential for kisspeptin to be used in the diagnosis and treatment of conditions such as Kallmann syndrome and CHH in certain cases.[41][42]

At present there are limitations to the potential therapeutic role of kisspeptin in CHH cases. Studies have shown that GnRH release, and hence LH and FSH response, does decrease over time with continuous kisspeptin administration and there have to be sufficient GnRH releasing neurones present in the hypothalamus in order for the kisspeptin to be effective. However, this is an ongoing area of research both with Kallmann syndrome and other clinical conditions linked to the dis-regulation of the HPG axis.

A failure of LH and FSH production to kisspeptin administration over a 24-hour period could be used as a diagnostic marker for Kallmann syndrome and CHH where there is an absence of GnRH releasing neurones.

There does appear to be a role in the use of kisspeptin in the treatment of acquired amenorrhoea in women and in some treatments of infertility.[43]

The two main international clinical and medical research groups for GnRH deficiency disorders are based at the Reproductive Endocrine Unit at Massachusetts General Hospital in Boston, USA and at the Department of Endocrinology, Diabetes and Metabolism at Centre hospitalier universitaire vaudois, Lausanne, Switzerland headed by Dr William Crowley and Prof. Nelly Pitteloud respectively.

See also

References

  1. 1 2 3 Boehm U, Bouloux PM, Dattani MT, et al. (2015). "Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism-pathogenesis, diagnosis and treatment.". Nat Rev Endocrinol. 11 (Jul 21): 547–64. PMID 26194704. doi:10.1038/nrendo.2015.112.
  2. 1 2 Guo CY, Jones TH, Eastell R (1997). "Treatment of isolated hypogonadotropic hypogonadism effect on bone mineral density and bone turnover.". J Clin Endocrinol Metab. 82 (2): 658–65. PMID 9024272. doi:10.1210/jcem.82.2.3758.
  3. ↑ Valdes-Socin H, Almanza MR, Fernández-Ladreda T, et al. (2014). "Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes". Frontiers in Endocrinology. 5: 109. doi:10.3389/fendo.2014.00109.
  4. ↑ Au MG1, Crowley WF Jr, Buck CL. (2011). "Genetic counseling for isolated GnRH deficiency.". Mol Cell Endocrinol. 346 (1–2): 102–9. PMC 3185214 Freely accessible. PMID 21664415. doi:10.1016/j.mce.2011.05.041.
  5. ↑ Schwanzel-Fukuda, M; Bick, D; Pfaff, DW (1989). "Luteinizing hormone-releasing hormone (LHRH)-expressing cells do not migrate normally in an inherited hypogonadal (Kallmann) syndrome.". Brain Res Mol Brain Res. 6 (4): 311–26. PMID 2687610. doi:10.1016/0169-328x(89)90076-4.
  6. 1 2 3 Mitchell AL, Dwyer A, Pitteloud N, Quinton R (2011). "Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory.". Trends Endocrinol Metab. 22 (7): 249–58. PMID 21511493. doi:10.1016/j.tem.2011.03.002.
  7. ↑ Kallmann FJ, Schönfeld WA, Barrera SE (1943–1944). "The genetic aspects of primary eunuchoidism.". Am J Ment Defic. 48: 203–236.
  8. ↑ synd/2549 at Who Named It?
  9. ↑ Maestre de San Juan, Aureliano (1856). "Teratolagia: falta total de los nervios olfactorios con anosmia en un individuo en quien existia una atrofia congenita de los testiculos y miembro viril.". El Siglo Médico. 3: 211–221.
  10. 1 2 Lee, Peter A.; Houk, Christopher P. (August 13, 2012). "The Smallest Kid in School: Evaluating Delayed Puberty". Medscape Pediatrics.
  11. 1 2 Fromantin M, et al. (1973). "[Impuberism and hypogonadism at induction into military service. Statistical study].". Probl Actuels Endocrinol Nutr. 16 (May): 179–99. PMID 4147392.
  12. 1 2 Laitinen EM1, Vaaralahti K, Tommiska J, Eklund E, Tervaniemi M, Valanne L, Raivio T. (2011). "Incidence, phenotypic features and molecular genetics of Kallmann syndrome in Finland.". Orphanet J Rare Dis. 6:41 (Jun 17): 41. doi:10.1186/1750-1172-6-41.
  13. 1 2 Pitteloud N, Quinton R, Pearce S, Raivio T, Acierno J; et al. (2007). "Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism". J Clin Invest. 117 (2): 457–63. PMID 17235395.
  14. ↑ Quinton R, Cheow HK, Tymms DJ, Bouloux PM, Wu FC, Jacobs HS (1999). "Kallmann's syndrome: is it always for life?". Clin Endocrinol (Oxf). 50 (4): 481–5. PMID 10468907. doi:10.1046/j.1365-2265.1999.00708.x.
  15. ↑ Laitinen EM, Tommiska J, Sane T, Vaaralahti K, Toppari J, Raivio T (2012). "Reversible congenital hypogonadotropic hypogonadism in patients with CHD7, FGFR1 or GNRHR mutations.". PLOS ONE. 7 (6): e39450. PMC 3378565 Freely accessible. PMID 22724017. doi:10.1371/journal.pone.0039450.
  16. ↑ Caronia LM, Martin C, Welt CK, Sykiotis GP, et al. (2011). "A genetic basis for functional hypothalamic amenorrhea.". N Engl J Med. 364 (3): 215–25. PMC 3045842 Freely accessible. PMID 21247312. doi:10.1056/NEJMoa0911064.
  17. ↑ Soo-Hyun Kim (2015). "Congenital Hypogonadotropic Hypogonadism and Kallmann Syndrome: Past, Present, and Future". Endocrinol Metab (Seoul). 30 (4): 456–466. PMC 4722398 Freely accessible. PMID 26790381. doi:10.3803/EnM.2015.30.4.456.
  18. ↑ Villanueva C (2015). "Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations". Genet Med. 17 (8): 651–659. doi:10.1038/gim.2014.166.
  19. ↑ Kirk JM. "Unilateral renal aplasia in X-linked Kallmann's syndrome". Clin Genet. 46 (3): 260–262. ISSN 0009-9163.
  20. 1 2 Bouvattier C, et al. (2011). "Neonatal gonadotropin therapy in male congenital hypogonadotropic hypogonadism.". Nature Reviews Endocrinology. 8 (3): 172–82. PMID 22009162. doi:10.1038/nrendo.2011.164.
  21. ↑ Laitinen EM, Hero M, Vaaralahti K, Tommiska J, Raivio T (2012). "Bone mineral density, body composition and bone turnover in patients with congenital hypogonadotropic hypogonadism.". Int J Androl. 35 (4): 534–40. PMID 22248317. doi:10.1111/j.1365-2605.2011.01237.x.
  22. ↑ Sidhoum VF, Chan YM, Lippincott MF, et al. (2013). "Reversal and Relapse of Hypogonadotropic Hypogonadism: Resilience and Fragility of the Reproductive Neuroendocrine System.". J. Clin. Endocrinol. Metab. 99: 861–70. PMC 3942233 Freely accessible. PMID 24423288. doi:10.1210/jc.2013-2809.
  23. ↑ Dwyer AA, Raivio T, Pitteloud N (2016). "MANAGEMENT OF ENDOCRINE DISEASE: Reversible hypogonadotropic hypogonadism.". Eur J Endocrinol. 174 (6): R267–74. PMID 26792935. doi:10.1530/EJE-15-1033.
  24. 1 2 Oxford Endocrinology Library. Testosterone Deficiency in Men. 2008. ISBN 978-0199545131 Editor: Hugh Jones. Chapter 9. Puberty & Fertility.
  25. 1 2 Male Hypogonadism. Friedrich Jockenhovel. Uni-Med Science. 2004. ISBN 3-89599-748-X. Chapter 3. Diagnostic work up of hypogonadism.
  26. ↑ Young J (2012). "Approach to the Male Patient with Congenital Hypogonadotropic Hypogonadism". J Clin Endocrinol Metab. 97 (3): 707–718. PMID 22392951. doi:10.1210/jc.2011-1664.
  27. ↑ Pitteloud N. (2012). "Managing delayed or altered puberty in boys.". BMJ. 345 (Dec 3): e7913. PMID 23207503. doi:10.1136/bmj.e7913.
  28. ↑ Bry-Gauillard H, et al. (May 2010). "Congenital hypogonadotropic hypogonadism in females: clinical spectrum, evaluation and genetics.". Ann. Endocrinol. (Paris). 71 (3): 158–162. PMID 20363464. doi:10.1016/j.ando.2010.02.024.
  29. ↑ Shaw ND, Seminara SB, Welt CK, Au MG, Plummer L, Hughes VA, Dwyer AA, Martin KA, Quinton R, Mericq V, Merino PM, Gusella JF, Crowley WF Jr, Pitteloud N, Hall JE (2011). "Expanding the phenotype and genotype of female GnRH deficiency.". J Clin Endocrinol Metab. 96 (3): E566–76. PMC 3047229 Freely accessible. PMID 21209029. doi:10.1210/jc.2010-2292.
  30. ↑ Quinton R. (2005). "Adolescent development: advice in ABC of adolescence is potentially misleading.". BMJ. 330 (7494: Apr 2): 789. PMC 555895 Freely accessible. PMID 15802728. doi:10.1136/bmj.330.7494.789.
  31. 1 2 Dunkel L, Quinton R (2014). "Transition in endocrinology: induction of puberty.". Eur J Endocrinol. 170 (6): R229–39. PMID 24836550. doi:10.1530/EJE-13-0894.
  32. ↑ Teixeira L, Guimiot F, Dodé C, Fallet-Bianco C, Millar RP, Delezoide AL, Hardelin JP (2010) Defective migration of neuroendocrine GnRH cells in human arrhinencephalic conditions. J Clin Invest, 120, 3668-3672 doi=10.1172/JCI43699 [doi]
  33. ↑ Han TS, Bouloux PM (2010). "What is the optimal therapy for young males with hypogonadotropic hypogonadism?". Clin Endocrinol (Oxf). 72 (6): 731–7. PMID 19912242. doi:10.1111/j.1365-2265.2009.03746.x.
  34. ↑ Eberhard Nieschlag, Pierre-Marc G. Bouloux, Barbara J. Stegmann, R. Ravi Shankar, Yanfen Guan, Anjela Tzontcheva, Christine McCrary Sisk, and Hermann M. Behre (2017). "An open-label clinical trial to investigate the efficacy and safety of corifollitropin alfa combined with hCG in adult men with hypogonadotropic hypogonadism". Reprod Biol Endocrinol. 15 (17). PMID 5341390. doi:10.1186/s12958-017-0232-y.
  35. ↑ Layman L. (2013). "Clinical Testing for Kallmann Syndrome.". J Clin Endocrinol Metab. 98 (5): 1860–1862. PMC 3644595 Freely accessible. PMID 23650337. doi:10.1210/jc.2013-1624.
  36. ↑ http://www.endocrine-abstracts.org/ea/0022/ea0022S17.3.htm
  37. ↑ Kallmann Syndrome and Idiopathic Hypogonadotropic Hypogonadism at eMedicine
  38. ↑ Brian Brett at abcbookworld
  39. ↑ Chadwick PM, Liao LM, Boyle ME (2005). "Size matters: experiences of atypical genital and sexual development in males.". J Health Psychol. 10 (4): 529–43. PMID 16014390. doi:10.1177/1359105305053420.
  40. ↑ Smith N, Quinton R (2012). "Kallmann syndrome.". BMJ. 345 (Dec 3): e6971. PMID 23207501. doi:10.1136/bmj.e6971.
  41. ↑ Skorupskaite K, George JT, Anderson RA (2014). "The kisspeptin-GnRH pathway in human reproductive health and disease.". Hum Reprod Update. 20 (4): 485–500. PMC 4063702 Freely accessible. PMID 24615662. doi:10.1093/humupd/dmu009.
  42. ↑ Jyothis T. George; Stephanie B. Seminara. "Kisspeptin and the Hypothalamic Control of Reproduction: Lessons from the Human". Endocrinology. 153 (11): 5130–5136. PMC 3473216 Freely accessible. PMID 23015291. doi:10.1210/en.2012-1429.
  43. ↑ Jayasena CN, Nijher GM, Abbara A, Murphy KG, Lim A, Patel D, Mehta A, Todd C, Donaldson M, Trew GH, et al. (2010). "Twice-weekly administration of kisspeptin-54 for 8 weeks stimulates release of reproductive hormones in women with hypothalamic amenorrhea.". Clin Pharmacol Ther. 88 (6): 840–847. PMID 20980998. doi:10.1038/clpt.2010.204.
OMIM Name Gene Locus Description
308700 KAL1 KAL1 (ANOS1) Xp22.3 Kallmann syndrome can be inherited as an X-linked recessive trait, in which case there is a defect in the KAL1 (ANOS1) gene, which maps at chromosome Xp22.3.[1][2]

This genetic form may include synkinesis and renal agenesis. ANOS1 encodes an extracellular matrix glycoprotein, anosmin-1, present in various embryonic tissues including the presumptive olfactory bulbs in the rostral forebrain. The protein is required to promote the embryonic migration of olfactory nerve fibres and GnRH neurons from the olfactory epithelium of the nose into the brain.[3][4]

147950 and 612702 KAL2 FGFR1 and FGF8 8p11.23 and 10q24.32 Autosomal dominant mutations of FGFR1, encoding fibroblast growth factor receptor 1, or FGF8, encoding one of its ligands (fibroblast growth factor 8), cause about 10% of KS/CHH cases. These genetic forms may include cleft lip and / or palate, hypodontia, hearing impairment, or ectrodactyly (FGFR1 mutations).[5][6][7]
244200 and 610628 KAL3 PROKR2 and PROK2 20p12.3 and 3p13 Mutations of PROKR2, encoding prokineticin receptor-2, or PROK2, encoding one of its ligands (prokineticin 2), are involved in autosomal recessive forms of KS (where both alleles of the gene are mutated), but most patients carrying mutations in either gene only have one mutated allele, suggesting that they carry at least one additional mutation in another, as yet unidentified in most cases, KS gene (oligogenic forms).[8]
616030 FEZF1 FEZF1 7q31.32 Mutations of FEZF1, encoding a (zinc finger)-domain containing protein, are involved in an autosomal recessive form of KS. The protein is required for the passage of growing olfactory nerve fibres and GnRH releasing neurones into the brain.[9]
612370 CHD7 CHD7 8q12.2 Mutations of CHD7 have first been reported in CHARGE syndrome, a severe developmental disease affecting multiple organs, which often includes KS. CHD7 encodes a transcriptional regulator that binds to enhancer elements in the nucleoplasm.[10]
611584 SOX10 SOX10 22q13.1 Mutations of SOX10 have first been reported in Waardenburg syndrome, which may include KS in addition to deafness. SOX10 encodes a transcription factor expressed by olfactory ensheathing cells, glial cells of neural crest origin that are permissive for the elongation and targeting of olfactory nerve fibres.[11]
614897 SEMA3A SEMA3A 7q21.11 Mutations of SEMA3A, encoding semaphorin 3A (ligand of plexin A1 receptor), involved in the guidance of olfactory nerve fibers into the brain, are thought to be involved in oligogenic forms of KS.[12][13]
614838 NELF NELF 9q34.3 Associated with the migration of the olfactory axons and GnRH neurones during development.
615271 FLRT3 FLRT3 20p12.1 Encodes fibronectin-like domain-containing leucine rich transmembrane protein 3. Protein associated with the function of the KAL2 genes (FGFR1 and FGF8) which allows for the migration of both olfactory axons and GnRH releasing neurones during early embryonic development.[14]
615270 FGF17 FGF17 8p21.3 Encodes fibroblast growth factor 17. Protein associated with the function of the KAL2 genes (FGFR1 and FGF8) which allows for the migration of both olfactory axons and GnRH releasing neurones during early embryonic development.[14]
615267 IL17RD IL17RD 3p14.3 Encodes interleukin receptor 17 D. Protein associated with the function of the KAL2 genes (FGFR1 and FGF8) which allows for the migration of both olfactory axons and GnRH releasing neurones during early embryonic development.[14]
615269 DUSP6 DUSP6 12q21.33 Encodes dual specificity phosphate-6. Protein associated with the function of the KAL2 genes (FGFR1 and FGF8) which allows for the migration of both olfactory axons and GnRH releasing neurones during early embryonic development.[14]
615266 SPRY4 SPRY4 5q31.3 Encodes sprouty, Drosphila, homolog of, 4. Protein associated with the function of the KAL2 genes (FGFR1 and FGF8) which allows for the migration of both olfactory axons and GnRH releasing neurones during early embryonic development.[14]
146110 and 614841 GNRHR and GNRH1 GNRHR and GNRH1 4q13.2 and 8p21.2 Biallelic mutations of GNRHR or GNRH1, encoding the GnRH receptor and the hormone GnRH1, respectively, cause normosmic CHH or partial CHH. Binding of GnRH1 to its receptor allows FSH/LH secretion by the pituitary gland.[15][16]
614837 and 614842 KISS1R and KISS1 KiSS-1R and KiSS-1 19p13.3 and 1q32.1 Biallelic mutations of KISS1R or KISS1, encoding the kisspeptin receptor 1 and the ligand kisspeptin 1, respectively, cause normosmic CHH. Kisspeptin, produced in the hypothalamus, is essential for pulsatile GnRH secretion, and is thought to be involved in the timing of the onset of puberty.<ref de Roux, N., Genin, E., Carel, J.C., Matsuda, F., Chaussain, J.L. and Milgrom, E. (2003) Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A, 100, 10972-10976</ref> <ref Seminara, S.B., Messager, S., Chatzidaki, E.E., Thresher, R.R., Acierno, J.S., Jr., Shagoury, J.K., Bo-Abbas, Y., Kuohung, W., Schwinof, K.M., Hendrick, A.G. et al. (2003) The GPR54 gene as a regulator of puberty. N Engl J Med, 349, 1614-1627</ref>.[17]
614840 and 614839 TACR3 and TAC3 TACR3 and TAC3 4q24 and 12q13.3 Biallelic mutations of TACR3 or TAC, encoding the receptor of neurokinin B and the ligand neurokinin B, respectively, cause normosmic CHH (usually severe HH with high incidence of micropenis). They are associated with a higher rate of reversible HH than mutations of other CHH genes. Neurokinin B, produced in the hypothalamus, is crucial for GnRH secretion.[18]
164160 LEP LEP 7q31.2 Encodes leptin, the ligand of the receptor LEPR. Involved in pulsatile GnRH secretion.
300200 DAX1/NROB1 DAX1 Xp21.2 Encodes a nuclear receptor with no known ligand. Known to be a transcription inhibitor. Mutations in DAX1 are thought to cause X-linked recessive forms of CHH in both males and occasionally females. Known to cause pubertal delay in females.
  1. ↑ Legouis R et al. (1991) The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules. Cell, 67, 423-435
  2. ↑ Franco B et al. (1991) A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature, 353, 529-536
  3. ↑
  4. ↑ Hardelin J-P & Dodé C (2016) FGFR1, FGF8, PROKR2, PROK2, ANOS1, and the olfactogenital (Kallmann) syndrome. Chapter 64 in Epstein’s Inborn errors of development: the molecular basis of clinical disorders of morphogenesis. 3rd edition. Erickson RP, Wynshaw-Boris A (eds) Oxford University Press. New York. pp 485-492./doi=10.1093/med/9780199934522.003.0064
  5. ↑ Dodé C et al. (2003) Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet, 33, 463-465
  6. ↑ Falardeau J, Chung WC, Beenken A, Raivio T, Plummer L, Sidis Y, Jacobson-Dickman EE, Eliseenkova AV, Ma J, Dwyer A, Quinton R, Na S, Hall JE, Huot C, Alois N, Pearce SH, Cole LW, Hughes V, Mohammadi M, Tsai P, Pitteloud N (2008). "Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice.". J Clin Invest. 118 (8): 2822–31. PMC 2441855 Freely accessible. PMID 18596921. doi:10.1172/JCI34538.
  7. ↑
  8. ↑ Dodé C, Teixeira L, Levilliers J, et al. (2006). "Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2". PLoS Genet. 2 (10): e175. PMC 1617130 Freely accessible. PMID 17054399. doi:10.1371/journal.pgen.0020175.
  9. ↑ | pmid = 25192046| year = 2014| author1 = Kotan| first1 = L. D.| title = Mutations in FEZF1 Cause Kallmann Syndrome| journal = The American Journal of Human Genetics| volume = 95| issue = 3| pages = 326–31| last2 = Hutchins| first2 = B. I.| last3 = Ozkan| first3 = Y| last4 = Demirel| first4 = F| last5 = Stoner| first5 = H| last6 = Cheng| first6 = P. J.| last7 = Esen| first7 = I| last8 = Gurbuz| first8 = F| last9 = Bicakci| first9 = Y. K.| last10 = Mengen| first10 = E| last11 = Yuksel| first11 = B| last12 = Wray| first12 = S| last13 = Topaloglu| first13 = A. K.| doi = 10.1016/j.ajhg.2014.08.006| pmc=4157145}}
  10. ↑ .<ref Jongmans MC et al. (2009) CHD7 mutations in patients initially diagnosed with Kallmann syndrome: the clinical overlap with CHARGE syndrome. Clin Genet, 75, 65-71 doi=10.1111/j.1399-0004.2008.01107.X
  11. ↑ Pingault V et al. (2013) Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness. Am J Hum Genet, 92, 707-724 doi=10.1016/j.ajhg.2013.03.024
  12. ↑ Hanchate NK, Giacobini P, Lhuillier P, Parkash J, Espy C, Fouveaut C, Leroy C, Baron S, Campagne C, Vanacker C, Collier F, Cruaud C, and 12 others. SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome. PLoS Genet. 8: e1002896, 2012. Note: Electronic Article. pmid=22927827
  13. ↑ Young J, Metay C, Bouligand J, Tou B, Francou B, Maione L, Tosca L, Sarfati J, Brioude F, Esteva B, Briand-Suleau A, Brisset S, Goossens M, Tachdjian G, Guiochon-Mantel A. SEMA3A deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system development. Hum. Reprod. 27: 1460-1465, 2012. pmid=22416012
  14. 1 2 3 4 5 Miraoui H1, Dwyer AA, Sykiotis GP, Plummer L, Chung W, Feng B, Beenken A, Clarke J, Pers TH, Dworzynski P, Keefe K, Niedziela M, Raivio T, Crowley WF Jr, Seminara SB, Quinton R, Hughes VA, Kumanov P, Young J, Yialamas MA, Hall JE, Van Vliet G, Chanoine JP, Rubenstein J, Mohammadi M, Tsai PS, Sidis Y, Lage K, Pitteloud N. (2013). "Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.". Am J Hum Genet. 92 (5): 725–43. PMC 3644636 Freely accessible. PMID 23643382. doi:10.1016/j.ajhg.2013.04.008.
  15. ↑ de Roux N, Young, J., Misrahi, M., Genet, R., Chanson, P., Schaison, G. and Milgrom, E. (1997) A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. N Engl J Med, 337, 1597-1602
  16. ↑ Bouligand, J., Ghervan, C., Tello, J.A., Brailly-Tabard, S., Salenave, S., Chanson, P., Lombes, M., Millar, R.P., Guiochon-Mantel, A. and Young, J. (2009) Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation. N Engl J Med, 360, 2742-2748
  17. ↑ Topaloglu, A.K., Tello, J.A., Kotan, L.D., Ozbek, M.N., Yilmaz, M.B., Erdogan, S., Gurbuz, F., Temiz, F., Millar, R.P. and Yuksel, B. (2012) Inactivating KISS1 mutation and hypogonadotropic hypogonadism. N Engl J Med, 366, 629-635
  18. ↑ Topaloglu AK et al. (2009) TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nat Genet, 41, 354-358
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