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. A range of other physical symptoms affecting the face, hands and skeletal system can also occur.
Cause The underlying cause is the defective migration of gonadotropin-releasing hormone (GnRH) expressing neurons (GnRH neurons) from the olfactory placode to the hypothalamus, leading to congenital GnRH deficiency. This leads to olfactory problems such as anosmia, optic defects like color blindness, and hypothalamic deficiencies associated with low levels of luteinising hormone (LH), affecting the sex hormone testosterone in males or oestrogen and progesterone in females. Diagnosis normally occurs during teenage years when puberty fails to start.
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.
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.
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 referral to a reproductive endocrinologist might be advisable.
The features of KS and other forms of HH can be split into two different categories; "reproductive" and "non-reproductive".
Reproductive features Failure to start or fully complete puberty Lack of testicle development in men (size <4 ml, whereas the normal range is between 12–25 ml) Primary amenorrhoea in women Poorly defined secondary sexual characteristics Micropenis in male cases In males, 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 women 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 Kallmann syndrome. Cleft palate, cleft 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 Increased incidence of color-blindness
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. In those cases, 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 (e.g. 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 but 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 10–22% of people, primarily cases of normosmic congenital hypogonadotropic hypogonadism (CHH) rather than KS cases and only found in people 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, 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.
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 (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.
The bone density scan is known as a dual energy X-ray absorptiometry scan (DEXA or DXA scan). It is a simple 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 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
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. In addition it is thought that some cases of KS/CHH are caused by two separate gene defects occurring at the same time.
Individual gene defects can be associated with specific symptoms which can help in identifying which genes to test for. Between 35 and 45% of cases of KS/CHH have an unknown genetic cause.
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.
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. 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. 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). 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.
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.
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.