What Is Kallmann Syndrome?

Overview

Puberty occurring late is known as delayed puberty, indicating no signs of sexual development until age 13 in girls and 14 in boys. One of the rare causes of delayed puberty is Kallmann syndrome (KS),  a genetic disorder and a form of hypogonadotropic hypogonadism, which is characterised by a delay or absence of puberty and a lack or impaired sense of smell. It is named after the German physician Franz Josef Kallmann.

The causes, symptoms, diagnosis, management, and treatment of KS are all covered in this article.

Causes of Kallmann syndrome

Kallmann syndrome is caused by inherited or idiopathic genetic abnormalities altering hypothalamic development and gonadotropin-releasing hormone (GnRH) secretion.¹ Several genes linked to Kallmann syndrome have been found. KAL1 gene mutations cause X-linked Kallmann syndrome, the most frequent type of disorder. It encodes a protein known as anosmin-1, involved in migrating GnRH neurons during embryonic development. Mutations in the FGFR1 gene (fibroblast growth factor receptor 1) can cause both X-linked and autosomal dominant Kallmann syndrome. The FGFR1 gene codes for a protein involved in the development of neurons, including GnRH neurons. Although these two mutations account for most KS cases, 35 to 45% of cases are not explained by the currently established genetic defects.²

Signs and symptoms of Kallmann syndrome

The most prominent characteristics of Kallmann syndrome are delayed or absent puberty and an impaired sense of smell (anosmia or hyposmia).³ Individuals with Kallmann syndrome frequently fail to undergo normal sexual maturation during adolescence, without secondary sexual traits such as breast development in people assigned female at birth or facial hair growth in people assigned male at birth. External genital growth might also be delayed. 

Another trait is the impairment of smell, which can range from a diminished ability to perceive smells (hyposmia) to a complete inability to smell (anosmia).³ The sense of taste can also be diminished because the smell is essential in flavour perception. 

Infertility is common in KS due to a lack of gonadotropin-releasing hormone (GnRH), resulting in decreased synthesis of sex hormones such as oestrogen in AFAB and testosterone in AMAB.⁴ Cleft lip or palate, hearing loss, renal agenesis, congenital heart diseases, dental, and skeletal abnormalities, including mirror hand motions (bimanual synkinesis), in which one hand's movements are mirrored by the other, may also be present. 

Remembering that the severity and specific combination of symptoms might differ across Kallmann syndrome patients is vital. 

Diagnosis

Diagnostic evaluation of Kallmann syndrome includes clinical assessment, hormone, and genetic testing. 

Firstly, history taking and a physical examination are performed, which checks for evidence of delayed puberty or an impaired sense of smell.

Blood tests evaluating hormone levels linked to puberty and reproductive function, such as luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and oestrogen, are critical for diagnosis. These hormone levels are generally low in persons with Kallmann syndrome.¹

Genetic testing is an essential part of the diagnosis procedure. Its goal is to detect particular gene variants linked to Kallmann syndrome. DNA sequencing can be used to evaluate significant genes known to be implicated in the disorder, such as the KAL1, FGFR1, PROK2, PROKR2, CHD7, and FGF8 genes. The identification of a pathogenic mutation can confirm the diagnosis of Kallmann syndrome while also providing vital information about inheritance patterns and potential consequences for family members.^1,2

Imaging investigations may be recommended in some circumstances to check the anatomy of the brain and discover any associated abnormalities. Magnetic resonance imaging ( MRI) can aid in establishing the diagnosis and ruling out other probable reasons by visualising parts of the brain like the hypothalamus, pituitary gland, and olfactory bulbs.

A timely diagnosis allows for the early starting of hormone replacement treatment, resolving reproductive issues, and managing accompanying symptoms. As a result, if Kallmann syndrome is suspected, it is critical to seek medical attention and consult with healthcare professionals experienced in diagnosing and managing the illness.

Management and treatment for Kallmann syndrome

The management and treatment of Kallmann syndrome generally focuses on the disorder's unique symptoms and complications. As Kallmann syndrome is caused by a lack of GnRH, hormone replacement therapy (HRT) is crucial.¹ These hormones are used to increase fertility and develop secondary sexual characteristics. For AMAB, testosterone replacement therapy promotes facial hair growth, muscle bulk, and the deepening of the voice. AFAB benefits from oestrogen and progesterone replacement therapy which promotes breast development, regulates menstruation, and helps the reproductive function.¹ 

The purpose of HRT is to mimic the normal hormonal balance that is absent in Kallmann syndrome patients.

Addressing the decreased sense of smell may be a different aspect of management. Olfactory training, which entails regular exposure to various odours to improve olfactory function potentially, may be advised. It can assist people in improving their ability to perceive odours and possibly improve their sense of taste.⁵ Counselling and support from mental health specialists can also help with the difficulties connected with Kallmann syndrome.

While many of Kallmann syndrome's symptoms and problems can be effectively addressed, it may not restore fertility in all cases. In this case, assisted reproductive technologies such as in vitro fertilisation (IVF) or the use of donated eggs or sperm may be considered.

Individuals with KS should have regular follow-ups with healthcare professionals specialising in endocrinology, reproductive medicine, and genetics. These professionals may test hormone levels, assure proper hormone replacement treatment dosing, and keep an eye out for any potential issues or changes in overall health.

FAQs

How can I prevent Kallmann syndrome?

As Kallmann syndrome is caused mostly by genetic mutations, it cannot be avoided through lifestyle changes or therapies. It is vital to emphasise that the condition is rare, and the probability of being affected by it is low. However, genetic counselling may be helpful if there is a family history of Kallmann syndrome. Genetic counselling entails analysing the risks of passing on genetic problems to offspring as well as addressing family planning and reproductive options.

How common is Kallmann syndrome?

Kallmann syndrome is considered a rare disorder, however, the exact prevalence is unknown. It is believed that 1:8000 AMAB and 1:40000 AFAB are affected in the overall population. The prevalence may vary between populations and geographical regions.

It's crucial to note that Kallmann syndrome can occasionally be misdiagnosed because its symptoms are mild and can be confused with other disorders. Furthermore, the wide range of clinical manifestations and genetic variation complicates correctly assessing its prevalence.

Who is at risk of Kallmann syndrome?

Kallmann syndrome is a genetic disorder, and both genetic and familial factors increase the possibility of getting the condition. A family history of the disease or associated genetic abnormalities is the key risk factor for Kallmann syndrome.

When should I see a doctor?

It is critical to see a doctor if you have concerns about delayed puberty, an impaired sense of smell, fertility problems or a family history of Kallmann syndrome. If you or your child has not undergone the expected physical changes of puberty, such as breast development or testicular growth, by the typical age, seek medical care. Furthermore, if you have a diminished sense of smell or are unable to identify odours, or if you are having difficulty conceiving, speaking with a healthcare professional specialising in endocrinology, genetics, or reproductive medicine can provide the essential assessment, diagnosis, and assistance. Addressing these concerns early can result in timely intervention, appropriate therapy, and improved results for Kallmann syndrome patients.

Summary

Kallmann syndrome is a rare genetic disorder characterised by delayed or absent puberty and an impaired sense of smell (anosmia or hyposmia). It is caused by genetic mutations affecting the development and function of the hypothalamus and resulting in a deficiency of gonadotropin-releasing hormone (GnRH). This leads to reduced production of sex hormones, infertility, and other related complications. The condition can be inherited in various patterns, including X-linked recessive. The severity and specific combination of symptoms can vary among individuals. Diagnosis involves a clinical assessment, hormone and genetic testing. Management typically involves hormone replacement therapy (HRT) to induce the development of secondary sexual characteristics and address fertility concerns. Olfactory training and psychological support may also be recommended. Early detection and diagnosis are vital for timely intervention and improved outcomes. While the condition cannot be prevented, seeking specialised medical care and genetic counselling can help individuals and families understand the risks, access appropriate care, and make informed reproductive choices.