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Kallmann syndrome (KS) is a genetic disorder that prevents a person from starting or fully completing puberty. Kallmann syndrome is one of a group of conditions termed hypogonadotropic hypogonadism. To distinguish it from other forms of hypogonadotropic hypogonadism, Kallmann syndrome has the additional symptom of a total lack of sense of smell (anosmia) or a reduced sense of smell. If left untreated, people will have poorly defined secondary sexual characteristics, show signs of hypogonadism, almost invariably be infertile and at increased risk of developing osteoporosis.

Epidemiology

The condition is more commonly diagnosed in males than in females. 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 epidemiology of Kallmann syndrome is not well understood. Individual studies include a 1986 report reviewing medical records in the Sardinian army which found a prevalence of 1 in 86,000 men.

Kallmann syndrome occurs about four times more often in males than females, but is only 2.5 times more common among males in familial cases.

Reproductive features

  • Failure to start or fully complete puberty
  • Manual synkinesis (mirror movements of hands)

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.

Functional hypothalamic amenorrhoea is seen in females where the HPG axis is suppressed in response to physical or psychological stress or malnutrition but is reversible with the removal of the stressor.

People with KS/HH lack the surge of GnRH, LH, and FSH that normally occurs between birth and six months of age, referred to as mini-puberty. 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 and 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. 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 (such as smoking) are involved, so the risk of developing it will vary from person to person. Bone density scans are recommended to monitor the bone mineral density.

Adequate calcium levels and, probably, more importantly, vitamin D levels are essential for healthy bone density. Some people 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 diseases.

Some people with severe osteoporosis might be prescribed bisphosphonates to preserve bone mass, in addition to hormone replacement therapy.

Genetics

thumb|upright=1.6|The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism

To date at least 25 different genes have been implicated in causing Kallmann syndrome or other forms of hypogonadotropic hypogonadism through a disruption in the production or activity of GnRH (37). 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.

The ANOS1 gene defect (previously known as KAL-1) was the first one discovered and the one most commonly tested for. It causes the x-linked form of Kallmann syndrome and is associated with the additional symptoms of anosmia, bimanual synkinesis and renal agenesis. This defect is thought to be responsible for between 5 and 10% of all Kallmann syndrome/CHH cases. 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).

Diagnosis

Diagnosis of Kallmann syndrome is based on clinical evaluation, endocrine testing, and genetic analysis. Hormone levels typically show low levels of sex steroids and gonadotropins. Diagnosing KS and other forms of CHH is complicated by the difficulties in distinguishing between a normal constitutional delay of puberty or a case of KS/CHH. The diagnosis is often one of exclusion found during the workup of delayed puberty.

In males, the use of age appropriate levels of testosterone can help to distinguish between a case of KS/CHH from a case of delayed puberty. If no puberty is apparent, especially no testicular development, then a review by a reproductive endocrinologist may be appropriate. If puberty is not apparent by the age of 16 then the person should be referred for endocrinological review. Post natal diagnosis of KS/CHH before the age of 6 months is sometimes possible as 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.

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.

thumb|Tanner scale-female

Diagnosis of KS/CHH normal involves a range of clinical, biochemical and radiological tests to exclude other conditions that can cause similar symptoms.

Clinical tests

  • Comparing height to standard growth charts
  • Determining the Tanner stage of sexual development. (Males with KS/CHH are normally at stage I or II with genitalia, females at stage I with breast development and both males and females at stage III with pubic hair development) Hormone replacement therapy is used to induce and maintain secondary sexual characteristics and fertility. For both males and females, the initial aim for treatment is the development of the secondary sexual characteristics normally seen at puberty. Once this has been achieved, continued hormone replacement therapy is required for both males and females to maintain sexual function, bone health, libido and general well being.

In females with KS/CHH, infertility is primarily due to the lack of maturation of eggs located within the ovaries. Ovulation induction can be achieved either with pulsatile GnRH therapy or alternatively with gonadotropin injections (hCG, FSH, hMG) given at set intervals to trigger the maturation and release of the egg for natural conception.

History

thumb|upright|[[Franz Josef Kallmann|Franz J. Kallmann, ]]

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 Spanish doctor Aureliano Maestre de San Juan in 1856, and sparse body and pubic hair

  • idiopathic/isolated hypogonadotropic hypogonadism (IHH)
  • normosmic hypogonadotropic hypogonadism (nHH)
  • hypothalamic hypogonadism
  • olfacto-genital syndrome

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 certain cases of Kallmann syndrome and CHH.

References

  • National Organization for Rare Diseases page on Kallmann syndrome