The Association Between Kallmann's Syndrome and Hypogonadotropic Hypogonadism

Written by Ben Bunting: BA, PGCert. (Sport & Exercise Nutrition) // British Army Physical Training Instructor // S&C Coach.


Anosmia and hypogonadism are common symptoms of Kallmann's syndrome, an inherited condition. The association between the two conditions was recognized in the 19th century by Maestre de San Juan.

During the twentieth century, a group of scientists, including Kallmann and Schoenfeld, redefined the condition and established that it is hereditary.


Kallmann's syndrome, also known as congenital hypogonadotropic hypogonadismic hypogonadism, is a rare genetic disorder characterized by an isolated deficiency of gonadotropin-releasing hormone (GnRH).

Individuals with KS tend to be infertile and not progress through puberty. Many male infants with KS also display cryptorchidism and a micropenis.

Additionally, individuals with this disorder usually exhibit anosmia.

The genetics of Kallmann's syndrome have not been fully elucidated. There are many factors that contribute to the occurrence of this disorder.

However, few of them have been identified with high-confidence. Mutations in FGFR1 or DUSP6 can lead to the disease.

Both Kallmann's syndrome and normo-syndromic isolated hypogonadism are genetic.

The main cause is an underdeveloped neuron in the hypothalamus, which is responsible for the release of gonad hormones. This hormone then triggers the development of egg and sperm cells.


Hypogonadotropic hypogonadism can be genetic, a trait shared by multiple relatives. Several genes, including those responsible for producing LH and FSH, may be involved in the disorder.

Neurotransmitters and hypothalamic dysfunction may also be involved. Other causes of hypogonadism may include physical exercise or use of sex steroids.

Genetic evaluation of HH probands can differentiate severe cases from milder ones. In patients with Kallmann syndrome, an MRI of the brain and pituitary may be necessary.

While the MRI of the brain and pituitaries is often helpful in the diagnosis of Kallmann syndrome, it is not necessary to rule out other causes. In some cases, reversal of hypogonadotropic hypogonadisa may occur, although this reversal may be short-lived.

In addition, there are several causes of isolated hypogonadotrophic hypogonadism, including chronic disease or rare disorders.

Kallmann's syndrome is caused by a mutation in the FGFR1 gene. FGFR1 is a single-spanning transmembrane receptor that expresses in GnRH neurons.

It contains three immunoglobulin-like domains, a heparin-binding domain, and two tyrosine kinase domains.

This mutation occurs in approximately seven to 10 percent of Kallmann's patients and has also been identified in some cases of normosmic IHH. However, this mutation exhibits variable expressivity and reduced penetrance.


The genetic basis of hypogonadotropic hypogonadismal syndromes is not known. However, a mutation in the FGFR1 gene, which causes Kallmann syndrome, reduces the function of FGFR1.

This prevents the proper transmission of signals and interferes with the migration of GnRH-producing nerve cells in the developing brain.

This leads to impaired production of sex hormones and delayed or absent puberty.

Mutations in the FGFR1 gene have been associated with a variety of other conditions.

For instance, some patients develop an abnormal lip or roof of the mouth, a defect in the development of their hands, and abnormalities of the hands and feet. Other genetic factors may also contribute to the development of these defects.


Hypogonadotropic hypogonadism is a condition in which the sex hormones LH, FSH, and/or LHRH are insufficient.

The condition can result in failure to enter puberty. In some cases, the condition may also result in normal puberty arrest.

The causes of Kallmann's syndrome and nIHH are unclear. There are a number of possible causes, including GnRH deficiency, a disorder that may occur after a gene mutation.

During embryonic development, a portion of the hypothalamus that produces GnRH migrates to the rest of the hypothalamus.

In people with Kallmann's syndrome, this part of the hypothalamus does not develop properly.

The result is a condition in which the brain does not produce enough GnRH, and therefore, does not produce enough gonadotropins to produce male hormones.

In most cases, patients with Kallmann syndrome have a deficiency of gonadotropin-releasing hormone (GnRH) that responds to pulsatile GnRH therapy.

In addition, hypothalamic-pituitary imaging does not reveal any space-occupying lesions. However, patients with Kallmann syndrome may suffer from severe anosmia and hyposmia.

In contrast, those with idiopathic hypogonadotropic hypogonadismal hypogonadism have a normal sense of smell.

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Several mutations in the FGFR5 gene are associated with Kallmann's syndrome and normo and hypergonadotropic hypogonadism (SHFM).

Mutations in FGFR1 are also associated with septo-optic-dysplasia and Kallmann's syndrome, and have been associated with SHFM and Kallmann's syndrome.

Mutations in this gene have also been linked to other inherited disorders, including limb-extremity dysplasia and septo-optic dysplasia.

Several studies have identified FGFR1 mutations as causal genes for IHH. Mutations in FGFR1 were associated with severe GnRH deficiency.

The study's authors also found that FGFR1 mutations were associated with Kallmann syndrome and normogonodiopathic IHH.


Hypogonadism is a condition in which the production of sex hormones is insufficient or non-existent.

It can be associated with or without disturbed gametogenesis and is caused by dysfunction of the hypothalamic-pituitary axis. The disorder can be reversible in some cases.

The cause of Kallmann's syndrome and nIHH is not yet clear. However, there are some genes that are implicated in this condition.

One gene is known as FGFR1. It is involved in the development of the face. Mutations in this gene result in abnormal morphogenesis of the olfactory bulb and craniosynostosis.

Idiopathic hypogonadotropic hypogonadismal disease is a rare condition caused by a deficiency of the hormone GnRH.

This disorder is hereditary and can affect either sex or reproduction. Both Kallmann's syndrome and normo-smic isolated hypogonadotropic hypogon adrenosis are associated with gene mutations.


Mutations in FGFR9, a gene that regulates FGF production, are associated with both complex and isolated modes of inheritance in Kallmann's syndrome and normasmic isolated hypogonadotropic hypogonodism (IHH).

These mutations are also contributors to the oligogenic genetic architecture of Kallmann's syndrome and IHH.

In one case report, a woman whose father died of a myocardial infarction at the age of 40 and two aunts' daughters both had hypogonadism.

Other symptoms included choanal atresia, delayed puberty, and deafness. The patient had abnormally low levels of FSH and estradiol.

Loss of FGFR1 is associated with several conditions, including CHH and Hartsfield syndrome.

The gene is conserved in both humans and other vertebrates. Mutations in FGFR1 result in decreased recruitment of FRS2a to FGFR1 and reduced MAPK signaling.


Mutations in FGFR10 have been associated with Kallmann's syndrome (KS), normosmic isolated hypogonadotropic hypergonadism (nIHH), and idiopathic hypogonadotropic hypogonadiss (IHH).

A study by Gurbuz et al. examined a total of 22 families with KS or nIHH and found that 17 (78%) carried a disease-associated mutation.

Among these families, seven (31.8%) had mutations in the GNRHR gene, six (27.2%) carried mutations in TACR3 and two (9%) carried mutations in KISSR. All 17 families had inherited this mutation in an autosomal recessive manner.

The gene FGFR10 plays an important role in regulating testosterone and ovulation. Its expression levels are linked with the levels of FSH and LH in the blood.

However, the role of FGFR10 in Kallmann's syndrome and normosmic isolated hypogonadotropic hypogonadism has not been fully understood.

The Association Between Kallmann's Syndrome and Hypogonadotropic Hypogonadism Conclusion

Hypogonadotropic hypogonadism is a rare genetic disorder that results in infertility. Treatment options include medically assisted procreation.

Genetic counseling is recommended for patients with this condition. The disease is genetically heterogeneous and results in incomplete gametogenesis when puberty should occur.

People with this disorder usually fail to reach sexual maturity, and they require lifelong hormone replacement therapy.

The cause of Kallmann syndrome is not fully understood. However, some cases have a genetic link to gonadotropin-releasing hormone deficiency.

A mutation in the fibroblast growth factor 8 gene has been identified in a subset of patients.

Some patients also have mutations in chromodomain-helicase DNA-binding protein 7 (CHD7), which may cause congenital cardiac defects.

Symptoms of Kallmann syndrome are not always apparent in the mother. Some cases of Kallmann syndrome are inherited from a mother who has a single altered copy of the ANOS1 gene in her cells. Other cases result from a new mutation in the gene.

Adult-onset hypogonadotropic hypogonadism occurs in males and is caused by lack of production of hypothalamic hormones that direct sexual development.

Males with this condition usually have small penises and undescended testes. Additionally, they do not develop secondary sex characteristics like facial hair. Females with hypogonadism may not develop breasts.

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