Introduction 

People with Kallman syndrome (KS) commonly experience a delay in their transition from childhood to adulthood (puberty) and an impaired sense of smell. KS can affect people assigned male at birth (AMAB) or female at birth (AFAB) with symptoms specific to their biological sex (more information about sex assigned at birth can be found here). In some cases, KS can also affect the mouth, ears, kidneys and heart.¹

The condition is caused by accidental changes (mutations) in a person’s genetic code, specifically in their DNA. This genetic code, or script, serves as a set of instructions that coordinates all aspects of development in a person’s body, including: the structure of the body, the timing of development, and the way different parts function. 

All these specific instructions are organised into sections called genes, which are essentially the instructional building blocks of your body. The human body has approximately 20,000 to 25,000 genes encoded in the DNA.²

There are 20 specific genes which, when accidentally changed, or ‘mutated’, have been associated with Kallman syndrome. Some individuals with KS express more than one KS-associated mutation.¹

The genes affected are involved in coordinating neurodevelopment (brain formation) before birth, raising the question: How can problems in early brain development cause the characteristic symptoms associated with KS? This article will explain how mutations in these neurodevelopmental genes can disrupt the wiring of the nervous system and critical endocrine (hormonal) pathways in Kallmann syndrome.

What is kallmann syndrome? 

KS is characterised by an absent/impaired sense of smell (anosmia/hyposmia) and absent/delayed puberty.

Symptoms of KS typically present as delayed sexual maturation during the anticipated stages of puberty. The physical and behavioural transition from child to adult during puberty is coordinated by chemical messengers called hormones. Sex hormones, in particular, play an important role in directing reproductive and sexual maturation.³

Kallmann Syndrome is caused by a lack of sex hormones during development (hypogonadotropic hypogonadism; HH). If a KS is suspected in an individual, healthcare providers can measure whether sex hormone levels are below those associated with typical development.³

Many people with KS are not aware of their impaired sense of smell until tested for the ability to detect odours with olfactory function testing. These tests can be accompanied by the imaging of olfactory bulbs in the brain, such as magnetic resonance imaging (MRI).³

These symptoms together are the defining characteristics of KS, distinguishing the disorder from other HH conditions that may show the same delays to puberty, but without the affected sense of smell. For example, puberty is disrupted in normosmic idiopathic hypogonadotropic hypogonadism (nIHH), but the sense of smell is unaffected in individuals with nIHH.⁴

What happens during typical puberty? 

Puberty is a complex process mediated by a coordinated system of organs and hormones, known as the hypothalamic–pituitary–gonadal (HPG) axis. During typical development, puberty is initiated by a hormone released from a region of the brain called the hypothalamus. 

This hormone, called gonadotropin-releasing hormone (GnRH), is secreted in bursts and stimulates the release of more hormones from other brain regions (the anterior pituitary gonadotropes).⁵

GnRH stimulates the release of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH).^6,7

• Luteinizing hormone (LH): LH works on sex-specific organs to produce and release their sex-specific hormones into the circulation
• Follicle-stimulating hormone (FSH): FSH supports LH with this function. In AFAB individuals, LH and FSH stimulate the ovaries to make oestrogen-related hormones. In AMAB individuals, LH and FSH prompt the testes to produce testosterone

For individuals who are AMAB:⁵ 

• Testosterone is the primary male sex hormone. During puberty in adolescence, testosterone levels increase and mediate the physical changes associated with transitioning from boyhood to manhood. This includes growth spurts, deeper voice, enlargement of the external reproductive characteristics (penis and testes), and body and facial hair growth

For individuals who are AFAB:⁵ 

• Oestrogen and progesterone are the two main female sex hormones. It drives physical changes such as breast development, body shape changes, and activates the development of the female reproductive system, coordinating menstruation

What goes wrong in kallmann syndrome?

Typical GnRH neuron development

During typical puberty, GnRH is released from specialised brain cells called GnRH neurons.

Neurons are nerve cells which function as wiring between different areas of the brain. These cells have long protrusions (called axons) which act like cables. GnRH neurons project from one area of the hypothalamus to another: the medial preoptic area to the median eminence.^5,8,9

This precise structure and wiring of the GnRH neurons depend on tightly coordinated processes during early stages of development, around the 5th and 16th embryonic weeks. 

GnRH are first formed in the olfactory placode (i.e., the nasal placode). It is a special area at the front of the developing baby’s head that will eventually form the external nose and olfactory (smell) processing centres. GnRH neurons formed at this location migrate inwards and upwards, using the axons of olfactory (smell-related) neurons as a scaffold, via branching of the vomeronasal nerve. They travel on a trajectory towards the developing hypothalamus. As embryonic development continues, they travel to their final position at the median eminence region of the hypothalamus.^9,10,11

Atypical GnRH neuron development in KS

Genetic mutations in individuals with KS impair the migration of GnRH neurons from the nasal placodes to the hypothalamus during development. The individual is born and remains without these neuronal connections into the expected transitional period between childhood and adolescent puberty.¹¹

Without innervation by GnRH from GnRH neurons during puberty, the hypothalamus is unable to stimulate the release of gonadotropins (LH and FSH) into the circulation. Improper stimulation of gonadotropins impairs the production of sex-specific hormones (oestrogen and progesterone, or testosterone), thereby delaying or preventing the sex-specific changes associated with puberty.

How does GnRH misrouting in KS affect the sense of smell?

Studies have suggested that the genetic mutations interfering with the migration of GnRH-producing neurons in early development also affect the movement of olfactory neurons during the same period. When olfactory nerve cells fail to reach the olfactory bulb, the sense of smell is reduced or completely lost.

What causes these changes in KS?

Mutations in key genes linked to kallmann syndrome

The instructions to build and run your body are written in your DNA, with genes acting like specific sections in that manual. A genetic "spelling mistake" changes the message in a gene, leading to a faulty or missing protein. In Kallmann syndrome, many of the identified mutations are related to neurodevelopment. 

ANOS1/KAL1 

The ANOS1 gene (also known as KAL1) acts as instructions for the body to make a protein called anosmin-1. Anosmin-1 plays important roles in:¹²

• GnRH neuron migration: facilitating the movement and outgrowth of axons during foetal development from the nasal placode to the future hypothalamus
• Cellular adhesion: Anosmin-1 is typically present within the intricate lattice of proteins and molecules coating neuronal cells, which can interact with those on the surfaces of other neurons/structures. The adhesion is important for the collective growth of neurons, so they may extend as bundles of cables

Fibroblast growth factor signalling: FGF8 & FGFR1

FGF8 and FGFR1 genes encode proteins involved in fibroblast growth factor (FGF) signalling. These pathways regulate:¹¹

• Timing of development: Early embryonic stem cells have the capacity to become any cell type. Combinations of chemical and structural cues are received by these undifferentiated cells to instruct what kind of cell these stem cells should become. FGF signalling maintains the undifferentiated state of early nerve cell precursors, leaving them as a ‘blank canvas’ until it is time for them to receive the cues to develop into nerve cells
• GnRH neuron formation: FGF8 is also critical for developing GnRH-producing neurons. If FGF8 levels are too low, these neurons may fail to develop or reach the brain properly

PROK2 & PROKR2

The PROK2 gene encodes a protein called prokineticin 2, while PROKR2 instructs the production of the prokineticin 2 receptor. Together they interact like two pieces of a jigsaw puzzle, whereby their connection continues signalling pathways involved in:^13,14

• GnRH neuron migration
• Olfactory bulb development: prokineticin 2 receptor signalling is important for spatial regulation (i.e., shaping) of the developing olfactory bulb

When mutations affect these genes, the resulting proteins may be missing, weakened, or unable to interact properly with other target cells or signalling components. Thus, critical neurodevelopmental stages are disrupted, leading to the two hallmark features of puberty and olfactory (sense of smell) in Kallmann syndrome.

Summary

Kallmann syndrome is caused by genetic mutations affecting the wiring of GnRH-producing and olfactory neurons. This occurs during the early stages of brain development. It affects the ability to process smell and further disrupts the brain-endocrine signalling pathways, which are responsible for controlling the important developmental process of puberty later on in life. 

FAQs

Is kallmann syndrome dangerous? 

• Kallmann syndrome itself does not reduce life expectancy, but health issues related to KS (e.g., heart conditions, osteoporosis, and reduced fertility) can have separate effects on a person's overall health and lifespan.¹⁵

Can kallmann syndrome be treated? 

The genetic mutation cannot be cured, but symptoms relating to puberty can be managed with hormone replacement therapy:

• For individuals who are AMAB, testosterone can be administered via injections, patches, or gels. HCG injections can be used to boost sperm production
• For individuals who are AFAB, oestrogen and progesterone can be attained via pills or patches. GnRH therapy can be used to stimulate ovulation to regulate irregular or absent menstrual cycles. HCG injections can be administered to support fertility³