Kallmann syndrome: overview and more

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Kallmann syndrome is a genetic disorder that causes difficulty in smelling and delayed or absent progression to puberty. The disease is often present at birth, but it may not be diagnosed until later in life. It is a rare disease that affects approximately 1 in 30,000 men and 1 in 120,000 women.

Kallmann syndrome belongs to a category of conditions called congenital hypogonadotropic hypogonadism (CHH, for short), a collection of conditions in which the brain does not release hormones that help trigger puberty. Kallmann syndrome accounts for about half of all cases of CHH.

Bad sense of smell is a key symptom in distinguishing Kallmann syndrome from other CHH conditions.

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Signs and symptoms of Kallmann syndrome

Classic symptoms of Kallmann syndrome are delayed or absent progression to puberty and impaired smell. The disease is most often diagnosed around the age of 14 to 16, when people seek medical advice because puberty doesn’t seem to be happening.

Other symptoms include:

  • Cleft lip or cleft palate
  • No kidney
  • Hearing loss
  • Shortened digits
  • Abnormal eye movements
  • Micropenis
  • Cryptorchidism (testes that do not descend before birth)
  • Bimanual synkinesia (when the movement of one hand is imitated by the other)

Kallmann syndrome is very similar to another genetic disorder called Normosmic Idiopathic Hypogonadotropic Hypogonadism (nIHH). People with nIHH can experience many of the same symptoms of puberty as people with Kallmann syndrome, but they have no difficulty with smell.

What are the causes of Kallmann syndrome?

Kallmann syndrome is caused by genetic mutations that affect the development of certain neurons in the brain. There are about 25 different genes linked to Kallmann syndrome, but the mutations out of the six listed below most commonly cause the disease:

  • ANOS1
  • CHD7
  • FGF8
  • FGFR1
  • PROK2
  • PROKR2

Known genetic mutations account for about 50% of Kallmann syndrome cases. The rest may result from unknown reasons or from undiscovered mutations.

How is Kallmann syndrome inherited?

Kallmann syndrome can be inherited in three ways.

In some cases, genetic mutations linked to Kallmann syndrome are inherited in an X-linked pattern. This means that men (who only have one X chromosome) only need one copy of a mutated gene to cause Kallmann syndrome, while women (who have two X chromosomes) need of two copies.

It also means that genetic fathers cannot pass the disease on to their sons. An example of a type of Kallmann syndrome inherited by this model is a form caused by mutations in the ANOS1 gene.

These genetic mutations can also be passed through an autosomal dominant pattern, meaning that only one affected genetic parent must have the gene to pass it on to a child. Kallmann syndrome due to genetic mutations in the genes listed below is often inherited in this way:

Finally, it can also be inherited in an autosomal recessive fashion, which means that two parents (who often have no symptoms) can have a child with Kallmann syndrome. Mutations in the PROKR and PROK2 genes can also be inherited in this way.

What are the symptoms of Kallmann syndrome?

In people with Kallmann syndrome, these genetic mutations alter the migration or function of certain nerve cells in the brain.

Before birth, olfactory neurons (neurons responsible for smell) and neurons responsible for releasing a puberty-stimulating hormone, gonadotropin releasing hormone (GnRH), form in the developing nose.

As the fetus grows, these neurons start to migrate from the nose to the brain, sneaking up to the hypothalamus, an area of ​​the brain that controls things we do without having to think about it, like releasing hormones, breathing, or controlling. the body. Temperature.

However, due to certain genetic mutations, these neurons do not appear to migrate properly during development in patients with Kallmann syndrome.

The result is that after birth, people with Kallmann syndrome may find it difficult to smell. It also means that the brain is not releasing GnRH at normal levels.

Without GnRH to trigger puberty, the testes and ovaries do not release other hormones often associated with this stage, such as follicle stimulating hormone (FSH, the hormone that stimulates egg development) or luteinizing hormone. (LH, the hormone that causes an egg). be released from the ovary).

Typically, these hormones cause the gonads to produce testosterone and estrogen, which in turn leads to the development of secondary sex characteristics (such as breast development, pubic hair growth, and body hair growth. face). In people with Kallmann syndrome, hormone replacement therapy may be needed to trigger the release of these hormones.

Diagnostic

Because it is a genetic disease, Kallmann syndrome is present at birth. However, many people are not diagnosed until puberty is supposed to be in full swing, between the ages of 14 and 16.

A doctor will start by asking about certain symptoms (such as delayed puberty) and smell. They could also perform the University of Pennsylvania odor identification test, in which they will ask the person to identify 40 different smells.

Biochemical tests are an essential part of the diagnosis of Kallmann syndrome. GnRH is not directly measurable in the body. Instead, a doctor will measure blood levels of hormones like LH, FSH, and sex steroid hormones like testosterone, estrogen, and progesterone.

A doctor may also order a magnetic resonance imaging (MRI) scan to study the hypothalamus, pituitary gland, and nose to look for reasons why odor and hormone levels may be wrong.

Finally, the diagnosis can be confirmed by genetic testing.

Processing

Treatment for Kallmann syndrome has two main goals: to help induce puberty and, later, to restart fertility.

The standard treatment for Kallmann syndrome begins with hormone replacement therapy. For men, this often means testosterone treatment. For women, this usually means treatment with estrogen and progesterone.

However, sometimes a doctor may prescribe a GnRH pump (pulsatile GnRH) or a combination of other hormones to stimulate the production of testosterone and estrogen.

The goal of this treatment, initially, is to help induce puberty and the development of secondary sexual characteristics. Hormone therapy is also important for maintaining bone density, which can decrease due to a lack of sex hormones.

Over time, some studies suggest that 10-20% of people with CHH regain their ability to produce such hormones on their own. However, these reversals may not last forever.

Later in life, people with Kallmann syndrome often find it difficult to have children without the help of treatment. But these treatments are generally straightforward and can help induce fertility.

Testosterone and estrogen / progesterone therapy alone will not induce fertility. But injections of hormones like FSH or LH, as well as synthetic forms of GnRH, can help restore fertility.

Some estimates suggest that fertility can be achieved in 75 to 80% of male patients. Therapies like pulsatile GnRH can also help stimulate ovulation in women. Assisted reproduction therapy is also an option for people with Kallmann syndrome who are looking to conceive.

Genetic counseling is also a consideration for people with Kallmann syndrome or who have family members with the disease and who want to understand the risk of their children inheriting it.

These treatments can reduce the burden of symptoms. However, they do not cure the underlying genetic causes of the disease.

Prognosis

Kallmann syndrome is not a fatal disease, but it usually lasts a lifetime.

Treatment can begin once patients are diagnosed. But many patients with Kallmann syndrome and other forms of CHH often go on a diagnostic odyssey (an unpredictable journey). In short, it takes time for clinicians to recognize Kallmann syndrome.

Kallmann syndrome is also a diagnosis of exclusion. This means that other conditions are ruled out before Kallmann syndrome is determined to be the underlying cause of the symptoms.

However, once the diagnosis is made, the symptoms can be managed well. With hormone replacement therapy, patients with Kallmann’s can enter puberty. Regular access to hormone replacement therapy can also reduce the risk of complications from low bone density.

Later in life, the challenges of Kallmann syndrome often focus on fertility. Although many patients are wrongly diagnosed as infertile, there are well-established treatments that can help restore fertility in both men and women.

To face

Aside from the physical manifestations of Kallmann syndrome, the condition can be difficult to manage logistically and emotionally. Patients reported feelings of isolation, lack of access to information about the disease, and difficulty finding specialist care.

A review article on the psychological aspects of Kallmann syndrome and CHH Notes estimates that 56% of women and 72% of men with Kallmann syndrome or other forms of CHH are teased because of their condition. Body image issues (such as body shame) have been reported in 93% of men and 80% of women with Kallmann syndrome.

Other surveys have noted that some patients have mild or even severe symptoms of depression.

Improving the emotional experience of Kallmann syndrome begins with early diagnosis, continued access to care, and access to mental health services. There are also patient support groups that can help people navigate the physical and emotional experience of Kallmann syndrome.

Summary

Kallmann syndrome is an inherited genetic disorder present at birth. This results in reduced or absent smell and delayed or absent puberty. Diagnostic tests include hormonal tests and genetic tests. Hormone therapy can trigger puberty and improve fertility.

A word from Verywell

Getting a diagnosis of Kallmann syndrome is emotionally difficult, especially if it’s not detected until late adolescence. However, there are well-established treatments that can manage most of the main symptoms and induce fertility. With early diagnosis, treatment, and support from peers and healthcare professionals, people with Kallmann syndrome can thrive.


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