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Kallmann syndrome is a genetic condition where the primary symptom is a failure to start puberty or a failure to fully complete it. It occurs in both males and females and has the additional symptoms of hypogonadism and almost invariably infertility. Kallmann syndrome also features the additional symptom of an altered sense of smell; either completely absent (anosmia) or highly reduced (hyposmia). Kallmann syndrome occurs when the hypothalamic neurons that are responsible for releasing gonadotropin-releasing hormone (GnRH neurons) fail to migrate into the hypothalamus during embryonic development. Kallmann syndrome is a part of a group of conditions that come under the term hypogonadotropic hypogonadism (HH). The sense of smell is only affected in approximately 50% of HH cases and these cases are termed Kallmann syndrome. Apart from the sense of smell there is no difference in the diagnosis or treatment of a case of HH or a case of Kallmann syndrome. The terminology used when describing cases of HH can vary. The term congenital hypogonadotropic hypogonadism (CHH) is now often used. Other terms used include idiopathic / isolated hypogonadotropic hypogonadism (IHH), normosmic hypogonadotropic hypogonadism (nHH) or hypothalamic hypogonadism. The term HH can be used to cover all cases, including Kallmann syndrome. The term isolated GnRH deficiency (IGD) has increasingly been used to describe these group of conditions as it highlights the primary cause of these conditions and to distinguish 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 methods. 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 woman 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 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 such as CHARGE syndrome. To date at least twenty five different genes have so far been implicated in causing Kallmann syndrome or other forms of HH through a disruption in the production or activity of GnRH. The 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 very problematic. Kallmann syndrome was described in a paper published in 1944 by Franz Josef Kallmann, a German-American geneticist. The link between anosmia and hypogonadism had already been noted however, in particular by the Spanish doctor Aureliano Maestre de San Juan in 1856. The condition is sometimes known by his name in Spanish speaking countries. The condition has a low prevalence, estimated as being between 1 in 4,000 and 1 in 10,000 for male HH cases overall and 1 in 50,000 for Kallmann syndrome. It is three to five times more common in males than females. Though whether this is a true gender imbalance or a reflection on how difficult KS / HH is to diagnose correctly, especially in females, has yet to be fully established. ==Signs and symptoms== The features of Kallmann syndrome (KS) and hypogonadotropic hypogonadism (HH) can be split into two different categories; "reproductive" and "non reproductive". Not all symptoms will appear in every case of KS/HH, not even amongst family members. Some of these features are linked to the gene defects known to cause KS/HH but in some cases it is still not clear why some of these features exist. It has been estimated that 60% of KS/HH cases will show a non-reproductive symptom. It is normally difficult to distinguish a case of KS/HH from a straightforward constitutional delay of puberty. However, if 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. Kallmann syndrome and hypogonadotropic hypogonadism do not exist as distinct conditions. Each case can show a different range of symptoms and a different severity of symptoms. Even family members will not always show the same degree of symptoms. Cases of KS/HH can be separated into different categories depending on the gene mutation(s) involved.〔〔 Severity can range from total absence of puberty with anosmia to slightly delayed puberty with or without anosmia. ;Classic HH This type of HH is present from birth and is lifelong. Approximately two-thirds of Classic HH 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 HH. Males with classic HH may also have had a history of un-descended testicles and/or micropenis. This type of HH has been shown to be caused by polyallelic mutations in males and females and autosomal dominant and x-linked recessive mutations in males mentioned in the table earlier in this article. ;Adult-onset HH This type of HH has only been shown to occur in males. The hypothalamic-pituitary-gonadal axis (HPG axis) functions normally at birth and well into adult life giving normal puberty. The HPG axis then 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 This type of KS/HH will appear to be the classic lifelong form at first but at some point in adult life the HPG axis resumes its normal function and GnRH, LH, and FSH levels return to normal levels. Has only been shown to occur in 10% of cases, primarily KS cases rather than HH cases and only found in patients who have undergone some form of testosterone replacement therapy. It is only normally discovered when testicular volume increases while on testosterone treatment alone and testosterone levels return to normal when treatment is stopped. This type of KS/HH rarely occurs in cases where males have had a history of un-descended testes and/or micropenis and has been shown to be caused by monoallelic mutations. ;Hypothalamic amenorrhoea This type of HH is seen in females where the HPG axis is suppressed in response to physical or psychological stress or malnutrition. It is reversible with the removal of the stressor. This type of HH is not associated with any non-reproductive symptoms and has been shown to be caused by monoallelic mutations. A study suggested that there may have been an evolutionary advantage at one stage in the early development of man for these genes to exist where it could have been an advantage for the females not to be fertile at times when food was scarce in the community. This type of HH has been shown to be caused by monoallelic mutations. 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Kallmann syndrome」の詳細全文を読む スポンサード リンク
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