Kallmann syndrome (KS) is a
genetic disorder that prevents a person from starting or fully completing
puberty
Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a ...
. Kallmann syndrome is a form of a group of conditions termed
hypogonadotropic hypogonadism
Hypogonadotropic hypogonadism (HH), is due to problems with either the hypothalamus or pituitary gland affecting the hypothalamic-pituitary-gonadal axis (HPG axis). Hypothalamic disorders result from a deficiency in the release of gonadotropic r ...
. 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
Secondary sex characteristics are features that appear during puberty in humans, and at sexual maturity in other animals. These characteristics are particularly evident in the sexually dimorphic phenotypic traits that distinguish the sexes of a ...
, show signs of
hypogonadism
Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low estroge ...
, almost invariably are
infertile
Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). It is the normal st ...
and are at increased risk of developing
osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone a ...
.
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 or activity of
gonadotropin-releasing hormone
Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released ...
by the
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus ...
. This results in low levels of the sex hormones
testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristi ...
in males or
oestrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal activ ...
and
progesterone
Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the majo ...
in females. Diagnosis normally occurs during teenage years when puberty fails to start.
Lifelong treatment for both sexes is normally required.
Hormone replacement therapy
Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. These symptoms can include hot flashes, vaginal ...
(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.
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.
Kallmann syndrome was first described by name in a paper published in 1944 by
Franz Josef Kallmann, a
German
German(s) may refer to:
* Germany (of or related to)
**Germania (historical use)
* Germans, citizens of Germany, people of German ancestry, or native speakers of the German language
** For citizens of Germany, see also German nationality law
**Ge ...
-
American
American(s) may refer to:
* American, something of, from, or related to the United States of America, commonly known as the "United States" or "America"
** Americans, citizens and nationals of the United States of America
** American ancestry, pe ...
geneticist
A geneticist is a biologist or physician who studies genetics, the science of genes, heredity, and variation of organisms. A geneticist can be employed as a scientist or a lecturer. Geneticists may perform general research on genetic processes ...
.
The link between anosmia and hypogonadism had already been noted by Spanish doctor
Aureliano Maestre de San Juan in 1856.
Signs and symptoms
![Jimmy_Scott](https://upload.wikimedia.org/wikipedia/commons/5/5a/Jimmy_Scott.jpg)
It is normally difficult to distinguish a case of Kallmann syndrome (KS)/hypogonadotropic hypogonadism (HH) from a straightforward constitutional delay of
puberty
Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a ...
. 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.
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 and 25 ml).
* Primary
amenorrhoea
Amenorrhea is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of mense ...
(failure to start
menstruation
Menstruation (also known as a period, among other colloquial terms) is the regular discharge of blood and mucosal tissue from the inner lining of the uterus through the vagina. The menstrual cycle is characterized by the rise and fall of ...
).
* Poorly defined secondary sexual characteristics.
* Micropenis in 5-10% of male cases.
*
Cryptorchidism
Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is from Greek () 'hidden' and () 'testicle'. It is the most common birth defect of the male genital tract. About 3% of ...
(undescended testicles) at birth.
* Low levels of the
gonadotropins
Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/chor ...
LH and
FSH.
*
Hypogonadism
Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low estroge ...
due to low levels of
testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristi ...
in men or
oestrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal activ ...
/
progesterone
Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the majo ...
in women.
*
Infertility
Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). It is the normal st ...
.
Non-reproductive features
* Total lack of sense of smell (
anosmia
Anosmia, also known as smell blindness, is the loss of the ability to detect one or more smells. Anosmia may be temporary or permanent. It differs from hyposmia, which is a decreased sensitivity to some or all smells.
Anosmia can be due to a nu ...
) 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
A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The ...
,
cleft lip
A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The te ...
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
Ectrodactyly, split hand, or cleft hand (derived from Greek ''ektroma'' 'abortion' and ''daktylos'' 'finger') involves the deficiency or absence of one or more central digits of the hand or foot and is also known as split hand/split foot malformat ...
), shortened middle finger (metacarpal)
or
scoliosis
Scoliosis is a condition in which a person's spine has a sideways curve. The curve is usually "S"- or "C"-shaped over three dimensions. In some, the degree of curve is stable, while in others, it increases over time. Mild scoliosis does not ty ...
* Manual
synkinesis
Synkinesis is a neurological symptom in which a voluntary muscle movement causes the simultaneous involuntary contraction of other muscles. An example might be smiling inducing an involuntary contraction of the eye muscles, causing a person to sq ...
(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. 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 to 22% of people, primarily normosmic CHH cases 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
The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...
at approximately 12 to 20 weeks
gestation
Gestation is the period of development during the carrying of an embryo, and later fetus, inside viviparous animals (the embryo develops within the parent). It is typical for mammals, but also occurs for some non-mammals. Mammals during pr ...
(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 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
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone a ...
or
osteopenia. Oestrogen (females) or testosterone (males) is essential for maintaining
bone density
Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although clinically it is measured by proxy according to optic ...
.
Deficiency in either testosterone or oestrogen can increase the rate of
bone resorption
Bone resorption is resorption of bone tissue, that is, the process by which osteoclasts break down the tissue in bones and release the minerals, resulting in a transfer of calcium from bone tissue to the blood.
The osteoclasts are multi-nuclea ...
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
An X-ray, or, much less commonly, X-radiation, is a penetrating form of high-energy electromagnetic radiation. Most X-rays have a wavelength ranging from 10 picometers to 10 nanometers, corresponding to frequencies in the range 30&nb ...
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
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...
levels and, probably, more importantly,
vitamin D
Vitamin D is a group of Lipophilicity, fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group ar ...
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
Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis. They are called bisphosphonates because they ...
to preserve bone mass, in addition to hormone replacement therapy.
Genetics
![The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism](https://upload.wikimedia.org/wikipedia/commons/5/5d/The_genetic_and_molecular_basis_of_idiopathic_hypogonadotropic_hypogonadism.jpg)
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
Inheritance is the practice of receiving private property, titles, debts, entitlements, privileges, rights, and obligations upon the death of an individual. The rules of inheritance differ among societies and have changed over time. Of ...
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
Sex linked describes the sex-specific patterns of inheritance and presentation when a gene mutation (allele) is present on a sex chromosome (allosome) rather than a non-sex chromosome (autosome). In humans, these are termed X-linked recessive, ...
form of Kallmann syndrome and is associated with the additional symptoms of
anosmia
Anosmia, also known as smell blindness, is the loss of the ability to detect one or more smells. Anosmia may be temporary or permanent. It differs from hyposmia, which is a decreased sensitivity to some or all smells.
Anosmia can be due to a nu ...
, bimanual
synkinesis
Synkinesis is a neurological symptom in which a voluntary muscle movement causes the simultaneous involuntary contraction of other muscles. An example might be smiling inducing an involuntary contraction of the eye muscles, causing a person to sq ...
and
renal agenesis
Renal agenesis is a medical condition in which one (unilateral) or both (bilateral) fetal kidneys fail to develop.
Unilateral and bilateral renal agenesis in humans, mice and zebra fish has been linked to mutations in the gene GREB1L. It has als ...
. This defect is thought to be responsible for between 5 and 10% of all Kallmann syndrome/CHH cases.
Pathophysiology
![GNRH1 structure](https://upload.wikimedia.org/wikipedia/commons/c/ce/GNRH1_structure.png)
The underlying cause of Kallmann syndrome or other forms of hypogonadotropic hypogonadism is a failure in the correct action of the hypothalamic hormone
GnRH
Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and releas ...
. 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
Klinefelter syndrome (KS), also known as 47,XXY, is an aneuploid genetic condition where a male has an additional copy of the X chromosome. The primary features are infertility and small, poorly functioning testicles. Usually, symptoms are sub ...
or
Turner syndrome
Turner syndrome (TS), also known as 45,X, or 45,X0, is a genetic condition in which a female is partially or completely missing an X chromosome. Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low h ...
which share some similar symptoms but have a different etiology.
The term hypogonadism describes a low level of circulating
sex hormones;
testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristi ...
in males and
oestrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal activ ...
and
progesterone
Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the majo ...
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
Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/ chorioni ...
hormones normally released by the
anterior pituitary gland
A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the p ...
known as
luteinising hormone
Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) ...
(LH) and
follicle stimulating hormone
Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, a ...
(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
The nasal placode (or olfactory placode) gives rise to the olfactory epithelium of the nose. Two nasal placodes arise as thickened ectoderm from the frontonasal process. They give rise to the nose, the philtrum of the upper lip, and the primary ...
, that will give rise to the olfactory epithelium; they then pass through the
cribriform plate
In mammalian anatomy, the cribriform plate (Latin for lit. ''sieve-shaped''), horizontal lamina or lamina cribrosa is part of the ethmoid bone. It is received into the ethmoidal notch of the frontal bone and roofs in the nasal cavities. It supp ...
, 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
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
Delayed puberty is when a person lacks or has incomplete development of specific sexual characteristics past the usual age of onset of puberty. The person may have no physical or hormonal signs that puberty has begun. In the United States, girls ...
.
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
Amenorrhea is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of mense ...
normally have to be investigated first before a case of KS/CHH is considered.
![Tanner scale-female](https://upload.wikimedia.org/wikipedia/commons/0/0c/Tanner_scale-female.svg)
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
The Tanner scale (also known as the Tanner stages or Sexual Maturity Rating (SMR)) is a scale of physical development in children, adolescents and adults. The scale defines physical measurements of development based on external primary and secon ...
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).
* Checking for micropenis and undescended testes (
cryptorchidism
Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is from Greek () 'hidden' and () 'testicle'. It is the most common birth defect of the male genital tract. About 3% of ...
) in males.
* Measuring testicular volume.
* Checking for breast development and age at
menarche
Menarche ( ; ) is the first menstrual cycle, or first menstrual bleeding, in female humans. From both social and medical perspectives, it is often considered the central event of female puberty, as it signals the possibility of fertility.
Gir ...
in females.
* Checking sense of smell using odorant panel or
University of Pennsylvania Smell Identification Test (UPSIT)
* Checking for hearing impairment.
* Checking for missing teeth or presence of
cleft lip
A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The te ...
and/or
cleft palate
A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The ...
.
* Checking for pigmentation of skin and hair.
* Checking for mirror movements of the hands or signs of
neurodevelopmental delay
Developmental disability is a diverse group of chronic conditions, comprising mental or physical impairments that arise before adulthood. Developmental disabilities cause individuals living with them many difficulties in certain areas of life, espe ...
.
Lab tests
* Early morning hormonal testing including
FSH,
LH,
testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristi ...
,
oestrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal activ ...
and
prolactin
Prolactin (PRL), also known as lactotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the pi ...
.
* GnRH and/or hCG stimulation test to determine activity of
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus ...
and
pituitary
In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The hypoph ...
.
* Sperm test
*
Liver function,
renal function and
inflammation marker testing.
*
Karyotype to check for chromosomal abnormalities.
Medical imaging
* Performing wrist
x-ray
An X-ray, or, much less commonly, X-radiation, is a penetrating form of high-energy electromagnetic radiation. Most X-rays have a wavelength ranging from 10 picometers to 10 nanometers, corresponding to frequencies in the range 30&nb ...
to determine bone age.
* Brain
MRI
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...
to rule out any structural abnormalities in the
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus ...
or
pituitary
In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The hypoph ...
and to check for presence of
olfactory bulbs
The olfactory bulb (Latin: ''bulbus olfactorius'') is a neural structure of the vertebrate forebrain involved in olfaction, the sense of smell. It sends olfactory information to be further processed in the amygdala, the orbitofrontal cortex (O ...
.
* Ultrasound of kidneys to rule out unilateral
renal agenesis
Renal agenesis is a medical condition in which one (unilateral) or both (bilateral) fetal kidneys fail to develop.
Unilateral and bilateral renal agenesis in humans, mice and zebra fish has been linked to mutations in the gene GREB1L. It has als ...
.
* Bone density scan (
DXA
Dual-energy X-ray absorptiometry (DXA, or DEXA) is a means of measuring bone mineral density (BMD) using spectral imaging. Two X-ray beams, with different energy levels, are aimed at the patient's bones. When soft tissue absorption is subtracted ...
) to check for
osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone a ...
or
osteopenia.
Treatment
![Kallmann treatment methods](https://upload.wikimedia.org/wikipedia/commons/1/18/Kallmann_treatment_methods.jpg)
For both males and females, the initial aim for treatment is the development of the
secondary sexual characteristics
Secondary sex characteristics are features that appear during puberty in humans, and at sexual maturity in other animals. These characteristics are particularly evident in the sexually dimorphic phenotypic traits that distinguish the sexes of a ...
normally seen at puberty.
Once this has been achieved, continued
hormone replacement therapy
Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. These symptoms can include hot flashes, vaginal ...
is required for both males and females to maintain sexual function, bone health,
libido
Libido (; colloquial: sex drive) is a person's overall sexual drive or desire for sexual activity. Libido is influenced by biological, psychological, and social factors. Biologically, the sex hormones and associated neurotransmitters that act u ...
and general wellbeing.
In males, testosterone replacement therapy is required for the maintenance of normal muscle mass.
Early treatment is sometimes required for male infants with suspected KS/CHH to correct undescended testes and
micropenis
Micropenis is an unusually small penis. A common criterion is a dorsal (measured on top) penile length of at least 2.5 standard deviations smaller than the mean human penis size (stretched penile length less than 9.3 cm (3.67 in) in adults). ...
if present with the use or surgery or
gonadotropin
Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/ chorioni ...
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.
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.
* Sex hormone replacement (testosterone or oestrogen & progesterone).
* Gonadotropin therapy (medications that replicate the activity of FSH and LH).
* GnRH pulsatile therapy.
Hormone replacement therapy
The method and dose of treatment will vary depending on the individual being treated. Initial treatment is normally made with lower doses in younger patients in order to develop the secondary sexual characteristics before adult doses are reached.
For males with KS/CHH the types of testosterone delivery include daily patches, daily gel use, daily capsules, subcutaneous or intramuscular injections or six-monthly implants. Different formulations of testosterone are used to ensure both the
anabolic
Anabolism () is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catabolism is the breaking ...
and
androgenic
An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This incl ...
effects of testosterone are achieved.
Nasal testosterone delivery methods have been developed but their use in KS/CHH treatment has not been formally evaluated.
Gonadotropin therapy, in the form of
human chorionic gonadotropin
Human chorionic gonadotropin (hCG) is a hormone for the maternal recognition of pregnancy produced by trophoblast cells that are surrounding a growing embryo (syncytiotrophoblast initially), which eventually forms the placenta after implantatio ...
(hCG) injections, with or without the use of FSH, can also be used in male patients to induce secondary sexual characteristic development alongside possible fertility induction.
For females, hormone replacement involves the use of oestrogen and progesterone. Firstly, oestrogen is used in tablet or gel form in order to maximise breast development, then a combination of oestrogen and progesterone is used.
Cyclical progesterone is normally required to help keep the
endometrium (lining of the
uterus
The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The ...
) healthy.
In males, the monitoring of treatment normally requires the measurement of serum testosterone,
inhibin B,
haematocrit
The hematocrit () (Ht or HCT), also known by several other names, is the volume percentage (vol%) of red blood cells (RBCs) in blood, measured as part of a blood test. The measurement depends on the number and size of red blood cells. It is nor ...
and
prostate-specific antigen
Prostate-specific antigen (PSA), also known as gamma-seminoprotein or kallikrein-3 (KLK3), P-30 antigen, is a glycoprotein enzyme encoded in humans by the ''KLK3'' gene. PSA is a member of the kallikrein-related peptidase family and is secreted b ...
(PSA). If injections are used, trough levels are taken to ensure an adequate level of testosterone is achieved throughout the injection cycle.
In females monitoring normally consists of measurement of oestrogen, FSH, LH,
inhibin B and
anti-Müllerian hormone
Anti-Müllerian hormone (AMH), also known as Müllerian-inhibiting hormone (MIH), is a glycoprotein hormone structurally related to inhibin and activin from the transforming growth factor beta superfamily, whose key roles are in growth differen ...
(AMH).
Standard hormone replacement therapy will not normally induce fertility in either males or females, with no testicular growth in males. Early treatment as adolescents can help with psychological well-being of people with KS/CHH.
Fertility treatments
Gonadotropin therapy can be used in both male and female patients in order to achieve fertility for some people.
Pulsatile GnRH therapy can also be used to induce fertility, especially in females, but its use is limited to a few specialist treatment centres.
In males with KS/CHH, infertility is primarily due to the lack of
sperm production within the
testes
A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testoste ...
. Sperm production can be achieved through either the use of GnRH administered via a microinfusion pump or through the use of gonadotropin injections (
hCG, FSH,
hMG). The time taken to achieve adequate sperm production for natural conception will vary from person to person. If the pre-treatment testes are very small and there has been a history of undescended testes it might take longer to achieve sperm production. In these cases,
assisted reproductive technology, such as sperm retrieval using
testicular sperm extraction
Testicular sperm extraction (TESE) is a surgical procedure in which a small portion of tissue is removed from the testicle and any viable sperm cells from that tissue are extracted for use in further procedures, most commonly intracytoplasmic sperm ...
(TESE) and/or
intracytoplasmic sperm injection
Intracytoplasmic sperm injection (ICSI ) is an in vitro fertilization (IVF) procedure in which a single sperm cell is injected directly into the cytoplasm of an egg. This technique is used in order to prepare the gametes for the obtention of em ...
(ICSI), might be required.
In females with KS/CHH, infertility is primarily due to the lack of
maturation of eggs located within the
ovaries
The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...
. 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.
Prognosis
Reversal of symptoms has been reported in between 10% to 22% of cases.
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.
Epidemiology
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
and a 2011 report from Finland which found a prevalence of 1:30,000 for males and 1:125,000 for females.
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.
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History
Kallmann syndrome was first described by name in a paper published in 1944 by Franz Josef Kallmann, a German
German(s) may refer to:
* Germany (of or related to)
**Germania (historical use)
* Germans, citizens of Germany, people of German ancestry, or native speakers of the German language
** For citizens of Germany, see also German nationality law
**Ge ...
-American
American(s) may refer to:
* American, something of, from, or related to the United States of America, commonly known as the "United States" or "America"
** Americans, citizens and nationals of the United States of America
** American ancestry, pe ...
geneticist
A geneticist is a biologist or physician who studies genetics, the science of genes, heredity, and variation of organisms. A geneticist can be employed as a scientist or a lecturer. Geneticists may perform general research on genetic processes ...
. The link between anosmia and hypogonadism had already been noted by the Spanish doctor Aureliano Maestre de San Juan in 1856. In the 1950s, De Morsier and Gauthier reported the partial or complete absence of the olfactory bulb
The olfactory bulb (Latin: ''bulbus olfactorius'') is a neural structure of the vertebrate forebrain involved in olfaction, the sense of smell. It sends olfactory information to be further processed in the amygdala, the orbitofrontal cortex ( ...
in the brains of men with hypogonadism.
Terminology
The terminology used when describing cases of HH vary and can include:
* GnRH deficiency
Isolated hypogonadotropic hypogonadism (IHH), also called idiopathic or congenital hypogonadotropic hypogonadism (CHH), as well as isolated or congenital gonadotropin-releasing hormone deficiency (IGD), is a condition which results in a small subs ...
* congenital hypogonadotropic hypogonadism
Isolated hypogonadotropic hypogonadism (IHH), also called idiopathic or congenital hypogonadotropic hypogonadism (CHH), as well as isolated or congenital gonadotropin-releasing hormone deficiency (IGD), is a condition which results in a small subs ...
(CHH)
* idiopathic/isolated hypogonadotropic hypogonadism
Isolated hypogonadotropic hypogonadism (IHH), also called idiopathic or congenital hypogonadotropic hypogonadism (CHH), as well as isolated or congenital gonadotropin-releasing hormone deficiency (IGD), is a condition which results in a small subs ...
(IHH)
* normosmic hypogonadotropic hypogonadism (nHH)
* hypothalamic hypogonadism
* olfacto-genital syndrome
Research
Kisspeptin
Kisspeptins (including kisspeptin-54 (KP-54), formerly known as metastin) are proteins encoded by the ''KISS1'' gene in humans. Kisspeptins are ligands of the G-protein coupled receptor, GPR54. ''Kiss1'' was originally identified as a human me ...
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
The KiSS1-derived peptide receptor (also known as GPR54 or the Kisspeptin receptor) is a G protein-coupled receptor which binds the peptide hormone kisspeptin (metastin). Kisspeptin is encoded by the metastasis suppressor gene KISS1, which is ex ...
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
External links
National Organisation for Rare Diseases page on Kallmann syndrome.
{{Authority control
Hypothalamus disorders
Syndromes affecting the endocrine system
Cell surface receptor deficiencies
Pituitary disorders
Rare genetic syndromes
Intersex variations