Researchers have identified two molecules that might be linked to Kallmann syndrome


A team of neuroscientists led by Professor Christiana Ruhrberg (UCL, UK) and Professor Anna Cariboni (University of Milan, Italy) have found two molecules that work together to help set up the sense of smell and pave the way to puberty in mice.

These findings, reported in the journal Development, may help our understanding of why patients with the inherited condition Kallmann syndrome cannot smell properly and cannot start puberty without hormone treatment.

Aficionados of 1990s jazz and fans of David Lynch’s Twin Peaks might remember the distinctive contralto vocals of “Little” Jimmy Scott. Jimmy’s naturally high singing voice was caused by a rare genetic disease, known as Kallmann syndrome, which affects about 1 in 30,000 males and 1 in 120,000 females.

Kallmann syndrome is caused by the lack of a hormone that stimulates the brain to produce signals needed to reach sexual maturity.

As a result, people with the condition don’t go through puberty and instead retain a child-like stature, no sex drive and underdeveloped genitals.

Currently, the most common treatment is hormone-replacement therapy to bypass the brain and kick-start puberty.

Unlike similar reproductive conditions, Kallmann syndrome patients also have no sense of smell – a tell-tale sign of this particular disorder.

Now, research has identified two molecules, called PLXNA1 and PLXNA3, that might be linked to the condition.

Scientists have found that both molecules are present in nerves that extend from the nose into the brain of developing mice.

These nerves transmit signals essential for the sense of smell and also guide hormone-secreting nerve cells from their place of origin in the nose to their destination in the brain, where they regulate the onset of puberty.

The study has revealed that both types of nerve are not wired properly when PLXNA1 and PLXNA3 are absent in developing mice.

Consequently, the brain regions that process smells are poorly formed and the brain also lacks the puberty-promoting nerve cells – the same symptoms shown by Kallmann syndrome patients.

This shows cells

The image contains a circular structure within the developing nose that gives rise to puberty-inducing nerve cells, shown in green.

Some of these nerve cells leave their birth place to travel in small clumps along nerve cables. These cells and the cables also have the PLXNA3 molecule, which is coloured red, but appears yellow, because of the red and green overlap. All cells are also highlighted in blue. The image is credited to Roberto Oleari, University of Milan.

“By studying the mouse as a model organism, we have identified a pair of genes that can cause an inherited condition with symptoms similar to human Kallmann syndrome.

This is an important finding, because the nerves that convey our sense of smell and that guide the puberty-inducing nerve cells arise in a very similar way during the development of mice and humans whilst they are still in the womb,” explained Professor Christiana Ruhrberg, who led the UK team.

This research gives hope to patients with an unknown cause of Kallmann syndrome by testing for defects in the PLXNA3 gene together with PLXNA1, which has been previously implicated. The lead author from the University of Milan, Professor Anna Cariboni added, “Although Kallmann syndrome can be treated with hormone injections if diagnosed early, knowing the underlying genetic causes can make a huge difference to speed up diagnosis and give treatment to the right patients at an earlier time.”

Funding: This research was funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC) and the Italian Fondazione Telethon.

Kallmann Syndrome (KS) is a congenital form of hypogonadotropic hypogonadism (HH) that manifests with hypo- or anosmia.

This decrease in gonadal function is due to a failure in the differentiation or migration of neurons that arise embryologically in the olfactory mucosa to take up residence in the hypothalamus serving as gonadotropin-releasing hormone (GnRH) neurons. A deficit in the GnRH hormone results in decreased levels of sex steroids leading to a lack of sexual maturity and the absence of secondary sexual characteristics.

Typical diagnosis occurs when a child fails to begin puberty. The condition, first described in 1944, is a rare pediatric genetic disease that is estimated to affect 1 in 48,000 individuals [1]

Treatment involves life-long hormone replacement therapy. However, treatment for male infants may include early hormone treatment or surgery to correct undescended testicles [2].  Unfortunately, later in life, these patients have an increased risk for developing osteoporosis due to their decreased sex hormones production and are often prescribed Vitamin D supplementation and bisphosphonates [3]

Kallmann syndrome, like other HH conditions, is characterized by reproductive features centered around a lack of sexual maturation during the years of puberty. These signs can include a lack of testicular development as determined by testicular volume in men, and a failure to start menstruation (amenorrhoea) in women. 

Poorly defined secondary sexual characteristics can include a lack of pubic hair and underdeveloped mammary glands.  Micropenis may also be present in a small portion of male cases, while cryptorchidism or undescended testicles may have been present at birth.

All of these traits are related to low levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), which consequentially results in low testosterone in males and estrogen and progesterone in women [2].

In addition to the reproductive deficits of HH conditions, there will also be the presence of other non-reproductive characteristics which are often defects of embryological origin. KS is defined by its additional presentation of anosmia or hyposmia. 

Approximately 60% of patients with GnRH deficiency present with an impaired sense of smell and could be identified as having KS, cleft palate and lip, hypodontia and cleft hand or foot are also frequently present along with unilateral renal agenesis [4].

Cerebral impairments may also be present, including central hearing impairment, mirror movements of the hands (synkinesis) and ataxia. Color-blindness and ocular window defects have also been observed [5][6].


Fundamentally, KS is the result of a defect in the GnRH neurons of the hypothalamus or their differentiation and migration to the hypothalamus during embryonic development.

The cause of this condition is genetic but can be the result of a multitude of different genetic mutations. Mutations in approximately 40 different genes have been reported to be connected with HH conditions including KS and present with slight variations in secondary features.

The most common defects related to KS are in the genes ANOS1 and FGFR1, but approximately 35 to 45% of cases are not explained by the currently identified genetic abnormalities [7].  Clinical genetic testing can be used to determine the specific genes involved in an individual patient. 

One gene of particular interest is the KISS1 gene encoding the kisspeptin signaling molecule. Kisspeptin is a potent initiator of the production of GnRH in the hypothalamus, and its production is known to be impacted by environmental factors [8].


One study of Kallmann Syndrome in Finland estimated the incidence of the condition within that country to be 1 in 48,000. The condition is genetic and often X-linked, resulting in increased prevalence among males.  Approximately 1 in 30,000 males has the condition compared to 1 in 125,000 females[1][9].


The KISS1/Kiss1 gene, which encodes for the kisspeptin hormone, is a well-known regulator of reproductive hormones, specifically acting upstream of GnRH [10][11]. Studies indicate that in some cases of HH, patients present with deletions and point mutations in the KISS1R [12][13]

The kisspeptin neuronal network” (KP) reside within the hypothalamus preoptic (POA) and the infundibular (INF) nuclei, respectively [14][12][13]. This elegant neuronal circuit regulates puberty and human reproductive functions by signaling GnRH secretion, subsequentially controlling FSH And LH.

The cranial nerve zero (0) has been described in the literature as an innocuous neuroanatomical structure associated with GnRH and potentially involved in the regulation of human reproductive functions and behaviors[15][16]. Perhaps, the CN0’s GnRH axons not only play a critical role in the development and differentiation of the HPA axis but may also trigger conceptually exhilarating endocrinologic responses independently or together with the KP neural circuit[15][16].

History and Physical

Medical history and genetic testing will often reveal many of the primary reproductive features of HH described above, along with non-reproductive features which will assist in differentiating between forms of HH such as KS with its characteristic deficit in the sense of smell. 


Evaluation usually occurs in conjunction with the first complaint of delayed development of adolescent puberty. Constitutionally delayed puberty or constitutional growth delay with prepubertal body proportions can be a normal condition that corrects itself through later onset of puberty and may be caused by some genetic and environmental factors.  During the evaluation of such patients, laboratory tests should be conducted to exclude hormonal deficiencies and other systemic syndromes.

Thyroxine and thyroid-stimulating hormone (TSH) levels, along with IGF-1 and gonadotropin levels (LH and FSH) would be normal with skeletal age in constitutionally delayed growth conditions but may be outside of the normal range in patients with a genetic disease. Urinalysis and routine blood work could also be used to screen these patients to identify inflammatory or autoimmune disorders. 

Also of note, patients that manage chronic pain with opioids have an increased association with induced hypogonadism later in life[17].

Treatment / Management

Kallmann Syndrome is usually treated pharmacologically with steroid replacement therapy such as testosterone or estrogen-progestin supplementation. Fertility can be increased using gonadotropin-based pharmacologic options. Complications of the condition may include osteoporosis, cardiac diseases, and psychological or neurological disorders and consultations with appropriate specialists should be considered if indicated.  Such associated conditions may show the need for dietary supplementation or physical therapy-based rehabilitation, among others.

Differential Diagnosis

Once laboratory testing has identified deviations in hormone levels, a genetic evaluation may narrow down the list of possible hypogonadotropic hypogonadism syndromes.  Kallmann syndrome is unique in that it is a hypogonadotropic hypogonadism syndrome characterized by hyposmia or anosmia.


Kallmann syndrome alone is not associated with decreased life expectancy, but the possible association with heart conditions, osteoporosis, and reduced fertility may impact the patient’s health and longevity separately. 


A variety of congenital heart disorders are reported in a small subset of KS patients, along with osteoporosis. The developmental of bone malformation is also possible and would be recognized from birth, such as cleft palate. Dry skin is also a potential complication of hypogonadic conditions such as KS. A patient may have had treatment for adrenocortical insufficiency in infancy or childhood.

The Compay of Biologists
Media Contacts:
Christiana Ruhrberg – The Compay of Biologists
Image Source:
The image is credited to Roberto Oleari, University of Milan.

Original Research: Closed access
“PLXNA1 and PLXNA3 cooperate to pattern the nasal axons that guide gonadotropin-releasing hormone neurons”. Roberto Oleari, Alessia Caramello, Sara Campinoti, Antonella Lettieri, Elena Ioannou, Alyssa Paganoni, Alessandro Fantin, Anna Cariboni, Christiana Ruhrberg.
Development doi:10.1242/dev.176461.


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