Kallmann Syndrome: The Complete Guide 

Take-home points

• Kallmann Syndrome affects approximately 1 in 30,000 males and 1 in 120,000 females.¹
• Up to 15% of patients with Kallmann Syndrome may experience spontaneous recovery.
• Successful fertility treatments have been reported in Kallmann Syndrome patients, with spontaneous pregnancy rates around 40% following appropriate intervention.
• Treatment delays in the UK are common due to doctors' reluctance to discuss hypogonadism, impacting timely care for affected individuals.
• Early diagnosis and treatment initiation are critical, as they significantly improve outcomes and quality of life for those living with Kallmann Syndrome.

What is Kallmann Syndrome?

Kallmann Syndrome (KS), or otherwise known as anosmic hypogonadism, is a rare genetic condition whereby the body does not make enough gonadotropin-releasing hormone (GnRH), a hormone required for the production of sex hormones in both genders.^1,2 If left untreated, people with Kallmann Syndrome will remain sexually underdeveloped, and infertile.  

There are two distinct features of Kallmann Syndrome that physicians look out for when prompting for diagnosis:

1. A lack of physical change / sexual development associated with puberty.
2. An impaired or absent sense of smell.  

Gonadotropin-releasing hormone causes the pituitary gland in the brain to make and secrete the hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In men, these hormones cause the testicles to produce testosterone; and in women, they cause the ovaries to make oestrogen and progesterone.³

A deficiency in GnRH is associated with a normal sense of smell in approximately 40% of affected individuals and an impaired sense of smell in approximately 60%. Only when the sense of smell is affected can it be classified as Kallmann syndrome.⁴

How Common is Kallmann Syndrome?

Kallmann syndrome occurs more often in males than in females, with figures showing it affects around 1 in 30,000 males and 1 in 120,000 females.¹ It's important to differentiate Kallmann Syndrome from a closely related condition, normosmic idiopathic hypogonadotropic hypogonadism (nIHH), which too causes problems during development and puberty, only without affecting the sense of smell.⁴

How Is Kallmann Syndrome Diagnosed?

So how do you tell the difference between these clinically identical conditions? Well, due to the noticeable lack of sexual development, diagnosis of Kallmann Syndrome is typically made by an endocrinologist when examining a patient going through puberty. However, signs such as undescended testicles or a small penis in infancy can also prompt early investigation.^1,2  

An endocrinologist can confirm a diagnosis through clinical examination, blood testing, imaging, and using the Tanner staging tool – an established diagnostic method used in the field of endocrinology to determine the development stage of certain sexual characteristics. In some cases, genetic testing may be requested to further assist in diagnosing various forms of this disease. ⁵

Symptoms of Kallmann Syndrome

From birth, males may exhibit features such as micropenis or undescended testicles, signalling early signs of the condition. However, the most noticeable symptoms typically arise at puberty due to the lack of sexual maturation.^1,2,5

Symptoms in Males:

• Little to no testicular growth.
• Decreased bone density.
• Reduced muscle mass.
• Erectile dysfunction.
• Low libido.
• Infertility.
• Micropenis.
• Undescended testes.

Symptoms in Females:

• Amenorrhea (absence of menstrual periods).
• Insufficient breast development.
• Infertility.

Symptoms Affecting Both Genders:

• Impaired or absent sense of smell (anosmia or hyposmia).
• Delayed or absent puberty signs.
• Decreased bone density (increasing the risk of osteoporosis).
• Non-reproductive features that may be present include:
  • Cleft lip or palate.
  • Hearing impairment.
  • Skeletal anomalies such as shortened digits.
  • Dental anomalies.
  • Ocular motor disturbances.
  • Renal anomalies.

Cause and Risk Factors

Most cases of Kallmann Syndrome are sporadic, meaning they occur randomly rather than being inherited. However, there are instances where the condition is passed down through families, with the mode of inheritance depending on the specific gene involved.^6,7

While researchers have successfully identified some of these genetic variations and understood their patterns of inheritance, there is still ongoing study looking at how and when we can pinpoint as to when these mutations occur. What is known, however, is that these genetic alterations can be inherited through several mechanisms:

• Autosomal recessive inheritance occurs when a child inherits the faulty gene from both parents, who are carriers but typically do not show symptoms themselves.
  
• Autosomal dominant inheritance refers to inheriting the mutation from just one parent, either the mother or the father.
  
• X-Linked Inheritance is used to describe the condition when females are the carriers, but males may exhibit the symptoms. A mother can pass the condition to her sons, while either parent may have daughters who are carriers.
  
• And, there is a newer understanding of genetic inheritance called oligogenic inheritance that suggests mutations in multiple genes may combine to cause the condition, adding another layer of complexity to its genetic origins.

Kallmann Syndrome Treatment

Currently there is no cure for Kallmann Syndrome, but there are treatments that are effective at managing the disease.² Treatment is usually lifelong and involves hormone replacement therapy, with further options available for those seeking fertility. Without treatment, most affected men and women are unable to have biological children due to infertility.¹  

However, getting the right treatment for Kallmann Syndrome can at times be difficult, given the rather private nature of the disease. This has led to a cultural hesitancy among many UK doctors to initiate discussions about hypogonadism, which inadvertently causes delays in treatment. This reluctance can make it challenging for patients to seek help, with some individuals only receiving treatment to induce puberty in their 40s.⁷

Learn more about hypogonadism: The Complete Guide

On the contrary, Kallmann Syndrome is considered a lifelong condition, about 10-15% of patients may experience spontaneous recovery of their hormonal system, though the reasons for this remain unclear.⁵  

Kallmann syndrome is not associated with decreased life expectancy and treated individuals have a normal appearance and function that is indistinguishable from individuals without the condition.⁶ Untreated, the condition can lead to various complications in adulthood, including decreased bone density, muscle mass, infertility, erectile dysfunction in males, and abnormal menstruation (amenorrhea) and insufficient breast development in females.  

Fertility Treatment

If fertility is affected, additional treatment with gonadotropins are necessary to stimulate the gonads.⁶ However, the effects can take up to two years to be apparent for men, whereas women may ovulate after just a week of treatment.⁷  

Although fertility can often be achieved, access to treatment poses significant challenges. Patients and healthcare providers may not be aware of the potential for normal fertility, and expertise in inducing spermatogenesis in men is limited.⁷ Success rates for spontaneous impregnation are around 40%, with an additional 20-30% success rate with in vitro fertilisation (IVF).^7,8

Support and Overall Wellbeing

Living with Kallmann syndrome requires management, but with the right medical support and information, individuals can lead healthy, normal and active lives.  

If you or your child show signs such as delayed puberty, an absent or reduced sense of smell, or in males, small testicles or undescended testes, it is advisable to consult a healthcare professional. Early diagnosis and treatment with hormone replacement therapy can prevent complications.

References

1. Kallmann syndrome: MedlinePlus Genetics. Accessed March 25, 2024. https://medlineplus.gov/genetics/condition/kallmann-syndrome/
2. https://www.rch.org.au/kidsinfo/fact_sheets/kallmann_syndrome_an_overview/. Accessed March 25, 2024.  
3. Definition of gonadotropin-releasing hormone - NCI Dictionary of Cancer Terms - NCI. Published February 2, 2011. Accessed March 25, 2024. 3
4. Hypogonadotropic hypogonadism 3 with or without anosmia - NIH Genetic Testing Registry (GTR) - NCBI. Accessed March 25, 2024. https://www.ncbi.nlm.nih.gov/gtr/conditions/C3550478/
5. Kallmann Syndrome - Symptoms, Causes, Treatment | NORD. Accessed March 25, 2024. https://rarediseases.org/rare-diseases/kallmann-syndrome/
6. Sonne J, Lopez-Ojeda W. Kallmann Syndrome. In: StatPearls. StatPearls Publishing; 2024. Accessed March 25, 2024. http://www.ncbi.nlm.nih.gov/books/NBK538210/
7. Smith N, Quinton R. Kallmann syndrome. BMJ. 2012;345:e6971. doi:10.1136/bmj.e6971
8. Morris GC, Lloyd-Evans E, Cahill DJ. Induction of spermatogenesis in men with hypogonadotropic hypogonadism. J Assist Reprod Genet. 2021;38(4):803-807. doi:10.1007/s10815-020-02058-0