What is kallmann syndrome?

The name ‘Kallmann’ is given after Franz Josef Kallmann, who was the first to describe it as a heritable genetic disorder in 1944, based on his findings in 3 families.¹ Kallmann syndrome(KS)  is a rare genetic disorder present since birth, where a child is either infertile or has delayed or incomplete puberty.¹ Moreover, there is partial or complete loss of smell (anosmia). This is due to the deficiency of gonadotropin-releasing hormone(GnRH), which is responsible for sexual development and maturity. The disease is seen in 1:8000 boys and 1:40000 girls, with underestimated values in women.²

What causes it?

40 types of genes have been associated with this disorder.¹ Mutation in genes such as KAL1 FGFR1 or FGF8 can affect the development and migration of gonadotropin-releasing hormone (GnRH) neurons and olfactory nerves (responsible for smelling sensation).^{1, 2} These GnRH neurons are first seen in the nose region of the fetus and then they migrate to the hypothalamus of the brain during the normal fetus development inside the womb.³

Mutated genes cause a deficiency in GnRH hormones and sex hormones responsible for growth and reproduction. ²

Classic features

• Micropenis (small size) or Cryptorchidism in males and amenorrhoea in females 
• Anosmia (loss of smell)
• Lack or delay in puberty
• Hypogonadotropic hypogonadism (lack of hormones that stimulate the ovaries and testes)

Non-reproductive features²

• Hand movements of one side mirror the other side unknowingly, also called bimanual synkinesis, seen in 4.1% to 31% of people⁴
• Abnormal eye movements,
• Congenital ptosis (drooping of the eyelid since birth) 
• Abnormal visual spatial attention( ability to judge how distant the object is)
• Hearing problems
• Agenesis of the corpus callosum(a tissue connecting two halves of the brain) leading to problems of muscle coordination, memory loss and learning difficulties²
• One side(occasionally bilateral) absence of kidneys (26.6% prevalence of kidney anomalies)⁴
• Cleft lip or palate (a split in the lip and palate of the mouth)
• Failure to form one or several teeth (hypodontia)
• Obesity

Other non-reproductive symptoms

Syndromes with overlapping features

• CHARGE Syndrome - 

Cause - CHD7 gene mutation

Common Features - hypogonadism ( delay in puberty or lack of it), loss of smell and hearing, and squint in the eye ¹⁰

Distinguishing features - ​​people with CHARGE syndrome have missing earlobes, defects inside the ears, autism and mental health problems like intellectual disability.¹⁰

• Waardenburg Syndrome Type IV - 

Cause - SOX10 gene mutation

Common Features - loss of smell, deafness, skin, hair and eye pigmentation, Hirschsprung disease and abnormal hands and legs.¹¹ SOX 10 gene mutation is sometimes seen in Kallmann syndrome.¹²

Distinguishing feature - Hirschsprung disease is not typically seen in KS. 

How to diagnose non-reproductive symptoms?

Diagnosis is largely based on clinical findings.

• Clinical History and Physical Examination - searching in people with KS and their first-degree relatives for tooth anomalies, palate, ear and nose abnormalities and skeletal anomalies like hand and leg deformities¹
• Audiological Assessment for loss of hearing¹
• Laboratory tests - 
  • Lower FSH, LH, and thyroid hormone levels are responsible for the delay in growth
  • Testosterone <100 ng/dL in males or estradiol <50 pg/mL in females is typical of KS¹
• Craniofacial and dental Imaging procedures (head, neck and face imaging) - 
  • Full mouth X-rays for anomalies of the teeth
  • CT scan of the head and neck region to analyse the hypothalamus and pituitary gland¹
  • Magnetic resonance imaging (MRI) for assessing the development of the olfactory bulbs of the nose and nasal tracts²
  • Bone age testing of the hand and wrist using X-rays. People with KS have a delayed bone age¹
• Renal Ultrasound - for analysing kidneys and anomalies related to them. Ultrasound of the foetus is done in families with a history of Kallman syndrome²
• Ultrasound to check for shrinking testes 
• Genetic Testing - sequencing of genes is done to find mutations and inheritance. People with autosomal dominant inheritance need genetic counseling because they are at a higher risk of transmitting KS to their children^1,13

Who does the assessment?

Multiple organs in the body can be affected which is why medical specialists are required for assessment, such as audiologist, ENT, endocrinologist, dentist, geneticist and neurologist.

How to treat this syndrome?

The main aim of the treatment is to gain secondary sexual characteristics, puberty, fertility, bone density and power in the muscles.¹³

• Hormone replacement therapy - to reverse the effects of hypogonadism (infertility and puberty delay).¹ Testosterone (males), and estrogen and progesterone (females) are given to stimulate the development of secondary sexual characteristics, breast development and growth of the penis.² Studies have shown that gonadotropin injections and hormone replacement therapy both restore fertility by promoting sperm growth and ovulation²
• Hearing aids and ear implants for hearing loss, depending on the intensity 
• Speech therapy for treating speech problems caused by tooth loss, high arch palate and cleft lip and palate
• Dental anomalies like malaligned teeth treated by an orthodontist with braces, and cleft lip and palate, need surgical treatment 
• Surgery to correct the position of the testicles¹⁴
• Monitoring and screening regularly for anomalies in the kidney, spine, hands and legs and neurological changes 
• Genetic counselling to prevent transmission to the next generation¹³
• Providing mental health support and psychiatric counselling to address problems of low self-esteem, learning challenges and psychosexual effects of loss of puberty¹³

How does it affect the quality of life?

• Both reproductive and nonreproductive symptoms can negatively impact a person's physical and mental development, and their behaviour and attitude towards life. It can also progress to psychosocial issues, which require psychiatric counselling¹⁵
• It is important to diagnose it early in life and address the problem promptly 
• With comprehensive treatment and care, a person with Kallman syndrome can live a normal and fulfilling life

Recent advances in the diagnosis and treatment of KS

The focus is now on revolutionary and advanced tests to identify new genes and prevent transmission of genetic diseases in the early stages, to the offspring.¹⁶

• New generation gene sequencing technologies³ - sequencing of multiple samples of genes in parallel has led to the discovery of newer ones responsible for KS¹⁶
• Diagnosis done when the foetus is in the womb (prenatal) can prevent birth defects and transmission of the mutated genes in the next generation¹⁶
• Preimplantation genetic testing (PGT) is done in people trying to have children through IVF(test tube babies), to prevent transmission of hereditary disease to the child in early stages¹⁶
• Bioinformatic analysis of the genes in olfactory(nose) or GnRH cells is done to identify new factors involved in the disease³

Unsolved questions

• How does KS affect females? What is the prevalence?
• Is the loss of smell without hypogonadism a clinical form of KS?
• What are the genes involved, and how many exactly are responsible for the olfactory and GnRH system interaction

Summary

Although Kallmann syndrome is an uncommon condition, it can have profound negative effects on the person suffering from it as well as their families. Special attention should be paid to early diagnosis through clinical examination and ruling out other possible syndromes. The non-reproductive symptoms are treatable, and a person can live a satisfying life. However, multiple long-term studies are required for understanding the varied and complex role of genes.  

 FAQS

Is kallmann syndrome reversible?

Studies have shown that in some people, hypogonadism (seen in Kallmann syndrome) is reversed after hormone therapy is withdrawn, called reversible Kallmann syndrome.¹⁷

What are the psychological issues associated with it?

Depression, anxiety, low self-esteem and self-contempt are seen in people with Kallmann syndrome, which affect their overall wellbeing and happiness.  

Can kallmann syndrome cause reduced life expectancy?

Complications associated with Kallmann syndrome, like osteoporosis, heart problems, cleft lip and palate and infertility, can affect health and overall life span

What are the symptoms of kallmann syndrome seen in females?

Irregular periods, mood swings, loss of smell, missing kidneys and weight gain are some of the symptoms seen in females