Kallmann syndrome (KS) is a genetic disorder that prevents a person from starting or fully completing puberty. If left untreated people with Kallmann syndrome will have poorly defined secondary sexual characteristics, show signs of hypogonadism, almost invariably be infertile and be at increased risk of developing osteoporosis. A range of other physical symptoms affecting the face, hands and skeletal system can also occur.
The underlying cause is a failure in the correct production of the GnRH hormone by the hypothalamus. This results in low levels of the sex hormones testosterone in males or oestrogen and progesterone in females. Diagnosis normally occurs during teenage years when puberty fails to start. Kallmann syndrome is a form of a group of conditions termed hypogonadotropic hypogonadism. Kallmann syndrome has an additional symptom of a total lack of sense of smell or a reduced sense of sense of smell which distinguishes it from other forms of hypogonadotropic hypogonadism.
Treatment for both males and females is normally required life long. Hormone replacement therapy (HRT) is the major form of treatment with the aim to replace the missing testosterone or oestrogen and progesterone. Specialised fertility treatments are also available.
A 2011 study of the Finnish population produced an estimated incidence of 1 in 48,000 people overall, with 1 in 30,000 for males and 1 in 125,000 for females. The condition is more commonly diagnosed in males than in females. Kallmann syndrome was first described by name in a paper published in 1944 by Franz Josef Kallmann, a German-American geneticist. The link between anosmia and hypogonadism had already been noted by the Spanish doctor Aureliano Maestre de San Juan in 1856.
Video Kallmann syndrome
Signs and symptoms
It is normally difficult to distinguish a case of KS / HH from a straightforward constitutional delay of puberty. However, if puberty has not started by either age 14 (girls) or 15 (boys) and one or more of the non-reproductie features mentioned belowe is present then a referral to reproductive endocrinologist might be advisable.
The features of Kallmann syndrome (KS) and other forms of hypogonadotropic hypogonadism (HH) can be split into two different categories; "reproductive" and "non reproductive".
Reproductive features
- Failure to start or fully complete puberty in both men and women.
- Lack of testicle development in men (size < 4 ml, whereas the normal range is between 12 and 25 ml).
- Primary amenorrhoea (failure to start menstruation).
- Poorly defined secondary sexual characteristics in both men and women.
- Micropenis in 5-10% of male cases.
- Cryptorchidism (undescended testicles) at birth.
- Low levels of the gonadotropins LH and FSH.
- Hypogonadism due to low levels of testosterone in men or oestrogen / progesterone in females.
- Infertility.
Non-reproductive features
- 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, hare lip or other midline cranio-facial defects.
- Neural hearing impairment
- Absence of one of the kidneys (unilateral renal agenesis)
- Skeletal defects including split hand/foot (ectrodactyly), shortened middle finger (metacarpal) or scoliosis
- Manual synkinesis (mirror movements of hands)
- Missing teeth (hypodontia)
- Poor balance or coordination due to cerebral ataxia.
- Eye defects such as coloboma or ptosis.
The exact genetic nature of each particular case of KS / HH will determine which, if any, of the non-reproductive features will occur. The severity of the symptoms will also vary from case to case. Even family members will not show the same range or severity of symptoms.
KS / HH is most often present from birth but adult onset versions are found in both males and females. The hypothalamic-pituitary-gonadal axis (HPG axis) functions normally at birth and well into adult life giving normal puberty and normal reproductive function. 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 tumour. This will lead to a fall in testosterone or oestrogen levels and infertility.
Functional hypothalamic amenorrhoea 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.
Some cases of KS / HH appear to reverse during adult life where the HPG axis resumes its normal function and GnRH, LH, and FSH levels return to normal levels. This occurs in an estimated 10 to 20% 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 / HH rarely occurs in cases where males have had a history of un-descended testes.
Affected individuals 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 gonadotrophin (hCG) produced by placenta at approximately 12 to 20 weeks gestation (pregnancy) which is normally unaffected by having KS or CHH.
People with KS / HH lack the surge of GnRH, LH, and FSH that normally 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. 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 normally 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. 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 person to person.
People 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.
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 to preserve bone mass. Exercise, especially weight bearing and resistance exercise, is known to reduce the risk of osteoporosis.
Maps Kallmann syndrome
Genetics
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.
The number of genes known to cause cases of KS / CHH is still increasing. In addition it is thought that some cases of KS / CHH are caused by two separate gene defects occurring at the same time. Around 50% of cases have an unknown genetic origin.
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.
Pathophysiology
The underlying cause of Kallmann syndrome or other forms of hypogonadotropic hypogonadism is a failure in the correct action of the hypothalamic hormone GnRH. This failure in GnRH activity can either be due to the absence of the GnRH releasing neurones inside the hypothalamus or the inability of the hypothalamus to release GnRH in the correct pulsatile manner to ensure LH and FSH release from the pituitary. 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.
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. 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.
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. 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.
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 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.
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.
Post natal diagnosis of KS / CHH before the age of 6 months is sometimes possible. The normal post natal hormonal surge of gonadotropins along with testosterone or oestrogen is absent in babies with KS / CHH. This lack of detectable hormones in the blood can be used as a diagnostic indicator, especially in male infants.
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. 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 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.
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 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.
Treatment
Treatment for KS and other forms of HH can be divided into hormone replacement therapy and 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 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 are 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 males with KS / CHH the types of delivery method available include daily patches, daily gel use, daily capsules, sub cutaneous or intramuscular injections or six monthly implants. Different formulations of testosterone are used to ensure both the anabolic and androgenic effects of testosterone are achieved.
Testosterone undecanoate is commonly used worldwide, though less so in the US, for treating male KS / CHH patients and has proved to be effective in maintaining good testosterone levels with an increased injection period of up to 12 weeks.
The precise treatment method used and interval between injections will vary from patient to patient and may need to be adjusted to maintain a physiological normal level of testosterone over a longer period of time to prevent the mood swings or adverse effects that can occur if testosterone levels are too high or low. Some treatments may work better with some patients than others so it might be a case of personal choice as which one to use.
As an alternative human chorionic gonadotrophin (hCG) can also be used to stimulate natural testosterone production. It acts in the same way as LH; stimulating the Leydig cells in the testes to produce testosterone. hCG can be used as pre-cursor to male fertility treatments but it can be used in isolation just for testosterone production.
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.
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.
Prognosis
Reversal of symptoms have been reported in between 15% to 22% of cases. 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 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.
Epidemiology
The epidemiology of Kallmann's is not well understood. Individual studies include a 1986 report reviewing medical records in the Sardinian army found a prevalence of 1 in 86,000 men and a 2011 report from Finland found a prevalence of 1:30,000 for males and 1:125,000 for females.
There is 4 to 5:1 ratio of men to women among all people with Kallmann syndrome; in familial Kallmann the ratio is lower, at 2.5 to 1.
Society and culture
Terminology
The terminology used when describing cases of HH can vary, other terms used to describe the condition include:
- GnRH deficiency
- congenital hypogonadotropic hypogonadism (CHH)
- idiopathic / isolated hypogonadotropic hypogonadism (IHH)
- normosmic hypogonadotropic hypogonadism (nHH)
- hypothalamic hypogonadism
- olfacto-genital syndrome
Patient perspective
Another aspect of Kallmann syndrome is social isolation. Since it is such a rare condition, many people with Kallmann syndrome have never met or talked with someone else with the condition. Doing so can help a person come to terms with having the condition.
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.
References
External links
- National Organisation for Rare Diseases page on Kallmann syndrome.
- European network for GnRH deficiency conditions. Information for patients, clinicians & researchers
- Rare Disease UK video on Kallmann syndrome.
- Man, 33, seeks puberty, the case of Lawrence Koomson, a physician who was treated for the condition as filmed in the documentary. (BBC)
Source of the article : Wikipedia
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