Kallmann Syndrome is an inherited form of hypogonadotropic hypogonadism, which means the genitals are small and puberty is delayed or absent due to a problem with the sex hormones. Kallmann Syndrome is unique because individuals cannot smell (anosmia) or have a diminished sense of smell (hyposmia). The diagnosis is usually made in adolescence because puberty is delayed or absent. Underdeveloped genitals and delayed puberty can be treated with hormone therapy. People with Kallmann syndrome are infertile, but this can also usually be treated with hormones.
Symptoms can vary widely, even among the same family (variable expressivity). Other possible symptoms include absence of one or both kidneys, a split in the lip or roof of the mouth called a cleft, abnormal movement of the hands where one mirrors the other (bimanual synkinesis), inability to hear, and missing teeth.
There are many types of hypogonadotropic hypogonadism (HH). Kallmann syndrome, a type of HH, has been divided into four different types.
There are many genes known to cause Kallmann Syndrome. There are multiple inheritance patterns including X linked, autosomal dominant, and autosomal recessive.
Kallmann Syndrome is also called congenital hypogonadotropic hypogonadism with anosmia, olfacto-genital pathological sequence, and idiopathic hypogonadotropic hypogonadism with anosmia.
Kallmann Syndrome can be abbreviated KS.
Frequently Asked Questions About Kallman syndrome/hypogonadotropic hypogonadism
Would a pituitary gland replacement be a cure for Kallman syndrome?
Kallmann syndrome is caused by too little Gonadotropin Releasing Hormone (GnRH) from the hypothalamus gland. GnRH from the hypothalamus is supposed to stimulate the pituitary gland to release (LH) and (FSH); which in turn act on the sex organs and gonads. It is the hypothalamus gland that is defective in Kallman syndrome, not the pituitary gland.
Why does Kallmann Syndrome affect more males than females?
Kallmann Syndrome affects males about four times as often as females. The reason for this is partly because of the way it can be inherited. In x-linked forms of Kallmann Syndrome, more men will be affected than women. This is because men only have one X-chromosome, so they only need to inherit one gene from one parent. Women have two X-chromosomes, so they would have to inherit two copies of the gene, one from mom and one from dad, which happens much less often. In addition, men tend to seek care for delayed puberty more often than females. Therefore, it may also be that more males are being diagnosed than females.
Why can people with Kallmann Syndrome have reduced bone density?
Low levels of sex hormones can decrease bone density. This can happen to people with Kallmann Syndrome who have low hormones for a long period of time or many short periods of time. If there is low bone density, a person with Kallmann Syndrome may need to seek treatment to avoid fractures and broken bones.
Who else in my family should I test for Kallmann Syndrome?
Who else in the family should be tested for Kallmann syndrome depends on the mode of inheritance. For example, if the gene is inherited in an x-linked manner, other males in the family should be tested. This can include brothers of an affected male and sons of an affected female. If the gene is autosomal recessive, it may be necessary to test siblings of an affected person. Parents of the affected person may also wish to be tested so that they may inform their siblings of carrier status. If the gene is autosomal dominant, it may be recommended to test parents, siblings, children, aunts and uncles. Check with your doctor or genetic counselor for more information about who should be tested based on the mode of inheritance.
Where do I find other people with Kallmann Syndrome ?
Check with your healthcare team for resources in your area. Because Kallmann Syndrome is rare, it may be difficult to find support groups in your area. There are support groups available for people with hypogonadotropic hypogonadism (HH) in general. There is a list of Yahoo and Facebook groups at the European GNRH Network site.
What specialist doctors should I see with Kallmann Syndrome?
People with Kallmann Syndrome should see an endocrinologist. These doctors specialize in the body’s hormones. They can help restore fertility and normal genitalia in people with Kallmann Syndrome by giving specific hormones. For trouble smelling, the may need to see an otolaryngologist, or ear-nose-throat doctor (ENT).
What is the usual abbreviation for Kallmann Syndrome?
Kallmann Syndrome can be abbreviated KS.
What is Kallmann Syndrome?
Kallmann Syndrome is an inherited form of hypogonadotropic hypogonadism, which means the genitals are small and puberty is delayed or absent due to a problem with the sex hormones. Kallmann Syndrome is unique because individuals cannot smell (anosmia) or have a diminished sense of smell (hyposmia). The diagnosis is usually made in adolescence because puberty is delayed or absent. Underdeveloped genitals and delayed puberty can be treated with hormone therapy. People with Kallmann syndrome are infertile, but this can also usually be treated with hormones.
Symptoms can vary widely, even among the same family (variable expressivity). Other possible symptoms include absence of one or both kidneys, a split in the lip or roof of the mouth called a cleft, abnormal movement of the hands where one mirrors the other (bimanual synkinesis), inability to hear, and missing teeth.
There are many types of hypogonadotropic hypogonadism (HH). Kallmann syndrome, a type of HH, has been divided into four different types.
There are many genes known to cause Kallmann Syndrome. There are multiple inheritance patterns including X linked, autosomal dominant, and autosomal recessive.
What is cryptorchidism and how does it affect fertility in Kallman syndrome??
Cryptorchidism is when the testicles stay in the abdomen instead of coming down into the scrotum. When this happens, males have a lesser chance of becoming fertile even with hormone replacement. About 38% of men with two undescended testicles are infertile, while about 10.5% of men with one undescended testicle are infertile. Your doctor should be aware of cryptorchidism because it also increases the risk of testicular cancer later in life.
What health problems should I look for in Kallmann Syndrome?
The first apparent health problem is loss of smell, but since most people are unaware that they lack this sense before testing, most individuals with Kallmann Syndrome are diagnosed in adolescence because of delayed puberty.
After puberty, it is important to look out for infertility, lack of sexual desire, difficulty with erections, and reduced bone density.
What happens because of that gene change in Kallmann Syndrome?
Genes associated with Kallmann Syndrome are important for development of the sense of smell and formation of the genitals. When these genes are disrupted, the nerves for smell do not travel to the nose. When these are absent, a person will not be able to smell or will have a reduced sense of smell. These genes also have instructions for cells that produce GnRH, which stands for gonadotropin-releasing hormone. Without this hormone, the body makes small and non-functional genitals.
What gene change causes Kallmann Syndrome?
Changes in many genes cause Kallman Syndrome. Examples include ANOS1, FGFR1, PROKR2, and PROK2, KAL1, NELF, FGF8, HS6ST1, CHD7, WDR11 and SEMA3A.
What does it mean to have inherited a “variant” in one of the genes for Kallmann Syndrome?
The genes associated with Kallmann Syndrome are also related to other disorders, such as normosmic idiopathic hypogonadotropic hypogonadism (nIHH). This disorder shares features with Kallmann Syndrome, except for lack of smell. Without knowing a person’s symptoms, it may be difficult to tell the difference between Kallmann Syndrome and other disorders based on the genes alone.
Having a variant in a gene associated with Kallmann Syndrome, means that a variation, or a genetic change has been found in an individual. When a gene is sequenced, to check for a change, it is compared to a ‘reference genomic sequence’. This means that the DNA in question is compared to "normal" DNA, or DNA that we know does not have a change in the Kallmann Syndrome genes.
Not all variants in the genes associated with Kallmann Syndrome cause Kallmann Syndrome. Variants are classified into one of three categories: benign, variant of unknown significance (VUS), or pathogenic.
Benign variants are changes that do not cause the disease. These changes can be seen in people without Kallmann syndrome. These benign changes are usually seen at a fairly high frequency among the general population. If a benign variant is found, this is not the reason for an individual’s Kallmann syndrome.
Variants of uncertain significance are changes that have not been seen enough before in the general population, or in people with Kallmann syndrome, to determine if it is causing the disease. In other words, these changes are uncertain. These variants may or may not be causing Kallmann syndrome. Usually, with time, variants of uncertain significance are reclassified as pathogenic or benign, as they are seen more frequently in individuals with Kallmann syndrome or in individuals in the general population. Medical management changes are rarely made based on a variant of uncertain significance.
Pathogenic variants are changes that are known to cause the disease. These changes have been seen in people with Kallmann syndrome and have not been seen in the general population at a high frequency. If a pathogenic variant is found, this is usually the reason for an individual’s Kallmann syndrome.
To learn more about your variant, contact a genetic counselor.
What does it mean to have a “variant” in the gene for Kallmann Syndrome?
The genes associated with Kallmann Syndrome are also related to other disorders, such as normosmic idiopathic hypogonadotropic hypogonadism (nIHH). This disorder shares features with Kallmann Syndrome, except for lack of smell. Without knowing a person’s symptoms, it may be difficult to tell the difference between Kallmann Syndrome and other disorders based on the genes alone.
Having a variant in a gene associated with Kallmann Syndrome, means that a variation, or a genetic change has been found in an individual. When a gene is sequenced, to check for a change, it is compared to a ‘reference genomic sequence’. This means that the DNA in question is compared to "normal" DNA, or DNA that we know does not have a change in the Kallmann Syndrome genes.
Not all variants in the genes associated with Kallmann Syndrome cause Kallmann Syndrome. Variants are classified into one of three categories: benign, variant of unknown significance (VUS), or pathogenic.
Benign variants are changes that do not cause the disease. These changes can be seen in people without Kallmann syndrome. These benign changes are usually seen at a fairly high frequency among the general population. If a benign variant is found, this is not the reason for an individual’s Kallmann syndrome.
Variants of uncertain significance are changes that have not been seen enough before in the general population, or in people with Kallmann syndrome, to determine if it is causing the disease. In other words, these changes are uncertain. These variants may or may not be causing Kallmann syndrome. Usually, with time, variants of uncertain significance are reclassified as pathogenic or benign, as they are seen more frequently in individuals with Kallmann syndrome or in individuals in the general population. Medical management changes are rarely made based on a variant of uncertain significance.
Pathogenic variants are changes that are known to cause the disease. These changes have been seen in people with Kallmann syndrome and have not been seen in the general population at a high frequency. If a pathogenic variant is found, this is usually the reason for an individual’s Kallmann syndrome.
To learn more about your variant, contact a genetic counselor.
What are the main symptoms of Kallmann Syndrome?
Kallmann Syndrome is characterized by lack of smell and delayed puberty. Males with Kallmann Syndrome can be born with a small penis and/or undescended testes, where the testicles remain in the abdomen instead of coming into the scrotum. Adult males can have decreased bone density, less muscle, small testes, less desire to have sex, difficulty with erections, and infertility.
Women with Kallmann Syndrome may not develop breasts, or the breasts may be smaller than normal. Most of the time, women do not have their period.
Less common symptoms include absence of one or both kidneys, a split in the lip or roof of the mouth called a cleft, abnormal movement of the hands where one mirrors the other (bimanual synkinesis), inability to hear, and missing teeth.
Is there Variable expression or incomplete penetrance in Kallmann Syndrome ?
There is variable expression, meaning that family members with the same gene change can have different symptoms. For example, some people with mutations in the PROK2 gene can have hearing loss, while others with changes in that gene will not have this symptom. There are no reports of incomplete penetrance, which would mean that some people with a gene change do not have any features of Kallmann Syndrome.
Is there one or two characteristic “odd” or “unusual” symptom or clinical feature of Kallmann Syndrome?
The feature that sets Kallmann Syndrome apart from other disorders that effect fertility is lack of or reduced ability to smell.
Is there newborn testing for Kallmann Syndrome?
Newborn screening is a state run program that screens babies at birth for certain serious medical conditions. There is no newborn screening offered for Kallmann syndrome.
If there is concern for Kallmann in a newborn, a special test can be ordered for that baby.
Usually, Kallmann Syndrome is diagnosed in adolescence due to delayed puberty. Sometimes, it is suspected at birth in males with undescended testes or a small penis. If a diagnosis of Kallmann Syndrome is suspected, a doctor can do DNA and hormone tests on the blood.
For further information about newborn screening, visit this [link url="www.babysfirsttest.org” target=”_blank”>website, or talk with your doctor or a genetic counselor.
Is there more than one test for Kallmann Syndrome?
There is more than one test for Kallmann syndrome. A blood test is necessary to look at hormone levels. Low levels of some hormones, such as pituitary gonadotropins, indicate the syndrome. The doctor will also test for absent or reduced sense of smell. It is also sometimes helpful to do an MRI, which will help look at structures inside the brain, including absent or small olfactory bulbs. These are necessary for smell. The diagnosis may also be confirmed with genetic testing.
Is there clinical research going on for Kallmann Syndrome?
Sometimes there are clinical research studies for Kallmann Syndrome. To find the most up to date list of clinical trials, go to: https://clinicaltrials.gov/ct2/results?term=kallmann&Search=Search
Is there a treatmen for Kallmann Syndrome?
Kallmann Syndrome itself cannot be cured, but delayed puberty and infertility can be treated with hormone replacement. Unfortunately, the sense of smell cannot be restored.
Is Kallmann Syndrome fatal?
Usually, people with Kallmann Syndrome can live long and fulfilling lives. It is only life-threatening when neither kidney develops. Without either kidney, a child will pass away at birth. Absence of the kidneys is rare in Kallmann Syndrome.
Is Kallmann Syndrome a lifelong disorder?
The symptoms of Kallmann Syndrome usually last for the entire lifetime of the individual. However, in 10-15% of people with the syndrome, the hormones will regain normal function. The reasons for this are unknown.
If I have Kallmann Syndrome, what should my doctor know about managing the disease?
Your doctor should be aware that people with Kallmann Syndrome have delayed puberty, or do not go through puberty at all. If this happens, hormone replacement may be necessary. In addition, fertility may be diminished because of Kallmann Syndrome. In this case, additional hormones may be prescribed. They should also know that the sense of smell may be diminished or absent.
People with Kallmann Syndrome can also have reduced bone density, so your doctor should be aware of this and help monitor bone strength. It is also important to continuously monitor hormone levels. This is because 10-15% of people with Kallmann Syndrome experience restoration of normal hormone levels without replacement. If this happens, hormone treatment will no longer be necessary.
If I have Kallmann Syndrome, what are the chances that they will find a gene change?
About half (50%) of people with Kallmann Syndrome and related disorders of sex hormones have a gene change that can be found. The rest may have multiple genes that contribute, or it could be “sporadic”, which means the cause is unknown.
I have Kallman syndrome. How large do the testicles usually have to be in order to be fertile?
In general, testicles need to be 8 mL (or 0.5 cubic inches) in order to produce enough sperm.
How is Kallmann Syndrome inherited?
There are three ways that Kallmann Syndrome is usually inherited: autosomal recessive, autosomal dominant, and x-linked.
Autosomal recessive: This means a person must have two changed copies of the gene, one from mom and one from dad, in order to have the disorder. Usually, we have two copies of every gene, one from each parent. In an autosomal recessive condition, if only one gene is changed, the person is considered a ‘carrier’. Carriers typically show no symptoms since the other copy of the gene is functioning normally. When two carriers have a child, there is a chance they could each pass on their changed copy. That child would then have no functioning copies of the gene, and therefore have the disorder.
Autosomal dominant: this means that a person only needs one copy of the gene to be changed in order to have Kallmann Syndrome. This is different than autosomal recessive. With an autosomal dominant disorder one changed gene is enough to cause symptoms. This could be inherited from one parent, or this could be a brand new change in that person.
X-linked: This means that the gene is on the X-chromosome. Females have two X chromosomes, and men have one X chromosome and one Y chromosome. In cases of X-linked inheritance, women must inherit 2 copies of the gene, one on each X, in order to have Kallmann Syndrome. Since men only have one X-chromosome, they only need to inherit one copy of the gene in order to have the syndrome.
Kallmann Syndrome can also be inherited in an “oligogenic” fashion, which means that multiple genes interacting with each other cause the disorder. Sometimes, Kallmann Syndrome can be sporadic, which means there is no gene change that can be found.
The way Kallmann syndrome is inherited depends on the gene. Each gene has a specific way of being inherited depending upon which chromosome it is found. Check with your doctor or genetic counselor for more information on your specific gene change.
How does hormone replacement work for Kallmann Syndrome?
An endocrinolost will determine the best hormone combination for the needs of each individual patient, based on the hormones the individual is lacking. It may be necessary to take the hormones by injection every few weeks for Kallmann Syndrome. Other hormones can be applied to the surface of the body, called topical hormones. These include patches, creams, and liquids. Hormones will need to be taken throughout life to maintain sexual characteristics.
How do I get tested for Kallmann Syndrome?
If Kallmann Syndrome is suspected, a blood test and imaging tests will be necessary. The blood test is necessary to look at hormone levels. Low levels of some hormones, such as pituitary gonadotropins, indicate the syndrome. The doctor will also test the sense of smell because this will be absent or reduced in people with Kallmann Syndrome. It is also sometimes helpful to do an MRI, which will help look at structures inside the brain, including absent or small olfactory bulbs. These are necessary for smell.
The diagnosis may also be confirmed with genetic testing. This is typically required in order to receive fertility treatment.
To learn more about genetic testing options, contact a genetic counselor. To find a genetic professional near you who can discuss genetic testing, visit the following two sites: A listing of medical geneticists can be found at the American College of Medical Geneticists website (www.acmg.net) and genetic counselors can be found on the National Society of Genetic Counselors website: www.nsgc.org.
How do I find clinical research in Kallmann Syndrome?
To find the most recent clinical trials, go to: https://clinicaltrials.gov/ct2/results?term=kallmann&Search=Search
How do I find a center of excellence in Kallmann Syndrome?
Currently, there are no specific centers of excellence for Kallmann syndrome. Most patients are cared for by a team which includes:
Endocrinology: Endocrinologists specialize in the body’s hormones. Specifically, reproductive endocrinologists can help restore fertility and genitalia in people with Kallmann Syndrome by giving specific hormones.
ENT: An ear nost and throat doctor, or an otolaryngologist may be useful for trouble smelling.
Does it matter if you test blood vs. saliva vs biopsy for Kallmann Syndrome?
Usually, a blood test is usually necessary in order to test for hormone levels. Blood is also typically used for genetic testing, however some labs will take other types of samples, such as saliva. Each laboratory’s requirements are different.
Does anything make Kallmann Syndrome worse?
There are no environmental factors that worsen the symptoms of Kallmann Syndrome.
Do people with Kallmann Syndrome have a good chance of reaching sexual maturity and achieving fertility?
Almost all patients with Kallmann Syndrome will achieve sexual maturity with the use of hormone replacement. Most patients can become fertile with hormones, but this is not guaranteed. One other reason for reduced fertility in males is when the testicles do not descend, called cryptorchidism. If the testicles are now brought down with surgery, the male may be infertile even with the assistance of hormone replacement.
Are there other organ specific concomitant treatments for Kallmann Syndrome ?
Delayed puberty and infertility can be treated with hormone replacement. Males with Kallmann Syndrome may take testosterone, follicle-stimulating hormone (FSH) and human chorionic gonadotropin (hCG) to help the penis and testicles reach a normal size and shape. In order to have children, men with Kallmann Syndrome must be able to form sperm, which can be induced by gonadotropin therapy.
Women with Kallmann Syndrome may need to take estrogen and progesterone to help with development of breats, genitals, and a normal period. In order to become fertile, females may need to take gonadotropin-releasing hormone (GnRH) and gonadotropins.
Are there other names for Kallmann Syndrome?
Kallmann Syndrome is also called congenital hypogonadotropic hypogonadism with anosmia, olfacto-genital pathological sequence, and idiopathic hypogonadotropic hypogonadism with anosmia.
Are there good support groups for Kallmann Syndrome ?
It may be difficult to find a support group specifically for Kallmann Syndrome because it is a rare disorder. There are support groups available for people with hypogonadotropic hypogonadism (HH) in general. Check with your healthcare team for in-person support groups in your area.
Are there forms of Kallmann Syndrome that aren’t genetic?
There are forms of Kallmann Syndrome where a gene change cannot be found, called “sporadic”. This means the cause is unknown. This could mean that these forms are not genetic, or it could mean that there is a gene for them that has not yet been discovered.
Are there earlier onset, later onset, or variant forms of Kallmann Syndrome?
There is variability in Kallmann Syndrome. The symptoms may vary depending on which gene is involved. For example, some people with a change in the FGFR1 gene can have missing teeth in addition to delayed puberty and small genitals.
Are there any other methods to achieve fertility besides taking hormones for Kallmann Syndrome?
If women with Kallmann Syndrome cannot become pregnant with hormone replacement alone, they can consider in vitro fertilization (IVF). This involves taking an egg from the female, fertilizing it with sperm from the male, monitoring the growth of the embryo, and placing the embryo into the woman’s uterus. With each cycle, there is about a 30% chance of becoming pregnant. If you are interested in this option, consult your doctor and seek a fertility clinic in your area.
Any other diseases that look a lot like Kallmann Syndrome?
Diseases with similar symptoms to Kallmann Syndrome include isolated congenital gonadotropin deficiency, CHARGE syndrome, adrenal hypoplasia congenita, congenital obesity syndromes, Bartlet-Biedl Syndrome and Moebius Syndrome. Normosmic idiopathic hypogonadotropic hypogonadism (nIHH) has similar features to Kallmann Syndrome, but individuals with this disorder have a normal sense of smell.
