Kallmann syndrome

Kallmann syndrome (KS) is a genetic disorder that prevents a person from starting or fully completing puberty. Kallmann syndrome is a form of a group of conditions termed hypogonadotropic hypogonadism.^[1] 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.^[2][3][4] If left untreated, people will have poorly defined secondary sexual characteristics, show signs of hypogonadism, almost invariably are infertile and are at increased risk of developing osteoporosis.^[2] A range of other physical symptoms affecting the face, hands and skeletal system can also occur.^[3]

The underlying cause is due to the defective migration of GNRH neurons from olfactory placode to hypothalamus, leading to congenital GNRH deficiency. This leads to olfactory problems such as anosmia, optic defects like color blindness, and results in hypothalmic deficiencies associated with low levels of LH, affecting sex hormone testosterone in males or estrogen and progesterone in females. Diagnosis normally occurs during teenage years when puberty fails to start.^[4] 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. ^[5]

Lifelong treatment for both sexes is normally required. 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.^[6] The Hormone replacement therapy is used to induce and maintain secondary sexual characteristics and fertility.^[7]

The condition is more commonly diagnosed in males than in females.^[8] 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.^[9] Kallmann syndrome was first described by name in a paper published in 1944 by Franz Josef Kallmann, a German-American geneticist.^[10][11] The link between anosmia and hypogonadism had already been noted by Spanish doctor Aureliano Maestre de San Juan in 1856.^[12][13]

Kallmann syndrome is caused by mutations in several genes involved in the development of the hypothalamus and olfactory bulbs, including KAL1, FGFR1, FGF8, PROKR2, and PROK2. These mutations disrupt the migration of GnRH-producing neurons from the olfactory placode to the hypothalamus during embryonic development.^[14]

It is normally difficult to distinguish a case of Kallmann syndrome (KS)/hypogonadotropic hypogonadism (HH) from a straightforward constitutional delay of puberty. However, if puberty has not started by either age 14 (girls) or 15 (boys) years and one or more of the non-reproductive features mentioned below is present, then a referral to reproductive endocrinologist might be advisable.^[15][2][8]

The features of KS and other forms of HH can be split into two different categories; "reproductive" and "non-reproductive".^{[4][13][6][16][3]}

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.^[26][27]

The number of genes known to cause cases of KS/CHH is still increasing.^[16] In addition it is thought that some cases of KS/CHH are caused by two separate gene defects occurring at the same time.^[8]

Individual gene defects can be associated with specific symptoms which can help in identifying which genes to test for.^[8][3] Between 35 and 45% of cases of KS/CHH have an unknown genetic cause.^[28]

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.^[8][3]

The underlying cause of Kallmann syndrome or other forms of hypogonadotropic hypogonadism is a failure in the correct action of the hypothalamic hormone GnRH. 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 different etiology.^[29] 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).^[16][28] Failure in GnRH activity can otherwise be due to the absence of the GnRH releasing neurons inside the hypothalamus. 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.^{[citation needed]}

In the first 10 weeks of normal embryonic development, the GnRH releasing neurons migrate from their original source in the nasal region and end up inside the hypothalamus. These neurons originate in an area of the developing head, the olfactory placode, that will give rise to the olfactory epithelium; 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 neurons towards the brain.^[30]

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.^[31][6][32] The diagnosis is often one of exclusion found during the workup of delayed puberty.^[33][34][35]

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.^[36] 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.^[37]

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.^[38]

Diagnosis of KS/CHH normal involves a range of clinical, biochemical and radiological tests to exclude other conditions that can cause similar symptoms.^{[citation needed]}

For both males and females, the initial aim for treatment is the development of the secondary sexual characteristics normally seen at puberty.^{[3][39][34][35][40]} 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 wellbeing.^[4] In males, testosterone replacement therapy is required for the maintenance of normal muscle mass.^[3]

Early treatment is sometimes required for male infants with suspected KS/CHH to correct undescended testes and micropenis if present with the use or surgery or gonadotropin or DHT treatment. Females with KS/CHH normally do not require any treatment before adolescence. Currently, no treatments exist for the lack of sense of smell, mirror movement of the hands or the absence of one kidney.^[4]

Treatment for both males and females with KS/CHH normally consists of one of three options which can be used for both hormone replacement therapy and/or fertility treatment.^[3][4]

• Sex hormone replacement (testosterone or oestrogen & progesterone).
• Gonadotropin therapy (medications that replicate the activity of FSH and LH).
• GnRH pulsatile therapy.

Reversal of symptoms has been reported in between 10% and 22% of cases.^[42][3]

Reversal cases have been seen in both KS and normosmic CHH but appear to be less common in cases of KS (where the sense of smell is also affected). Reversal is not always permanent and the precise genetic causes are not yet fully understood.^[43]

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^[44] and a 2011 report from Finland which found a prevalence of 1:30,000 for males and 1:125,000 for females.^[45]

Kallmann syndrome occurs about 4 times more often in males than females, but is only 2.5 times more common among males in familial cases.^[44][45]

The link between anosmia and hypogonadism was noted already in 1856 by the Spanish physician Aureliano Maestre de San Juan^[12] who described a 40-year old male who, upon autopsy, exhibited absent olfactory bulbs, undeveloped testicles, micropenis, and lack of pubic hair.^[11]

A 1961 case report by the Austrian pathologist Richard Ladislaus Heschl^[11] noted an association between male hypogonadism (including an unmasculinised larynx,^[46] and sparse body and pubic hair^[11]) and anatomical absence of the olfactory nerves, bulb, and tract. The case is later cited by Richard von Krafft-Ebing in his seminal Psychopathia Sexualis while discussing the role of olfaction in the physiology of the sexual response:^[46]

A case mentioned by Heschl [...] is remarkable, where the absence of both olfactory lobes was accompanied by imperfectly developed genitals. It was the case of a man aged 45, in all respects well developed, with the exception of the testicles, which were not larger than beans and contained no seminal canals, and the larynx, which seemed to be of feminine dimensions. Every trace of olfactory nerves was wanting, and the trigona olfactoria and the furrow on the under surface of the anterior lobes were absent. The perforations of the ethmoid plate were sparingly present, and occupied by nerveless processes of the dura instead of by nerves. In the mucous membrane of the nose there was also an absence of nerves.

— Richard von Krafft-Ebing, Charles Gilbert Chaddock (translator), Psychopathia Sexualis

In 1914, Franz Weidenreich performed autopsies on cadavers of 10 people who had had anosmia, uncovering hypogonadism in three and postulating a syndromic association.^[11]

The syndrome is named for Franz Josef Kallmann, a German-American geneticist, who, along with colleagues, described three family clusters of the syndrome in a 1944 paper, thus confirming a heritable, genetic basis of the syndrome. The cases described by Kallmann et al. also exhibited colour blindness, with some additionally exhibiting mental retardation.^[10][11]

In the 1954, De Morsier and Gauthier reported the partial or complete absence of the olfactory bulb in the brains of men with hypogonadism,^[47][13] proving that anosmia resulted from agenesis of the olfactory bulb.^[11]

The terminology used when describing cases of HH vary and can include:^{[citation needed]}

• GnRH deficiency
• congenital hypogonadotropic hypogonadism (CHH)^[48]
• idiopathic/isolated hypogonadotropic hypogonadism (IHH)
• normosmic hypogonadotropic hypogonadism (nHH)
• hypothalamic hypogonadism
• olfacto-genital syndrome

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.^[49][50]