What Is Kallmann Syndrome?

Kallmann syndrome is a genetic disorder that results in difficulty smelling and delayed or absent progression to puberty. The condition is often present at birth, but it may not be diagnosed until later in life. It’s a rare disease that affects about 1 in 30,000 males and 1 in 120,000 females. 

Kallmann syndrome falls into a category of conditions called congenital hypogonadotropic hypogonadism (CHH, for short), a cluster of conditions in which the brain doesn’t release hormones that help trigger puberty. Kallmann syndrome accounts for about half of all CHH cases.

The poor sense of smell is a key symptom to distinguishing Kallmann syndrome from other CHH conditions.

Kallmann Syndrome Signs and Symptoms

The classic symptoms of Kallmann syndrome are delayed or absent progression to puberty and an impaired sense of smell. The disease is most often diagnosed around the ages of 14–16, when people seek a doctor’s advice because puberty doesn’t seem to be occurring. 

Other symptoms include: 

• Cleft lip or cleft palate 
• Absence of a kidney 
• Hearing loss 
• Shortened digits 
• Abnormal eye movements 
• Micropenis 
• Cryptorchidism (testicles that don’t descend before birth) 
• Bimanual synkinesis (when the movement of one hand is mimicked by the other)

Kallmann syndrome is very similar to another genetic disease called normosmic idiopathic hypogonadotropic hypogonadism (nIHH). People with nIHH may have many of the same puberty-related symptoms as people with Kallmann syndrome, but they don’t have any difficulty with sense of smell. 

What Causes 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 mutations on the six listed below most frequently cause the condition: 

• 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 by undiscovered mutations.

How Is Kallmann Syndrome Inherited?

Kallmann syndrome can be inherited in three ways. 

In some cases, genetic mutations related to Kallmann syndrome are inherited in an X-linked pattern. That means males (who only have one X chromosome) only need one copy of a mutated gene to cause Kallmann syndrome, whereas females (who have two X chromosomes) need two copies. 

It also means that genetic fathers can’t pass on the condition to their sons. An example of a type of Kallmann syndrome inherited through this pattern is a form caused by mutations in the ANOS1 gene.

These genetic mutations may also be passed down through an autosomal dominant pattern, which means that only one affected genetic parent has to have the gene to pass it down to a child. Kallmann syndrome due to genetic mutations in the genes listed below are often inherited in this pattern: 

• FGFR1
• PROKR2
• PROK2
• CHD7
• FGF8

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

What Causes Kallmann Syndrome Symptoms?

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)—are formed in the developing nose. 

As the fetus matures, these neurons begin to migrate from the nose into the brain, snaking their way toward the hypothalamus—an area of the brain that controls things we do without having to think about them, like releasing hormones, breathing, or controlling body temperature. 

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

The result is that, after birth, people with Kallmann syndrome may have trouble smelling. It also means the brain doesn’t release GnRH at normal levels.

Without GnRH to kick puberty into gear, testicles and ovaries don’t release other hormones often associated with that stage, like follicle-stimulating hormone (FSH, the hormone that stimulates egg development) or luteinizing hormone (LH, the hormone that causes an egg to be released from the ovary).

Typically, those hormones drive the gonads to produce testosterone and estrogen, which, in turn, drive the development of secondary sexual characteristics (such as breast development, pubic hair growth, and facial hair growth). In people with Kallmann syndrome, hormone replacement therapy may be needed to prompt the release of these hormones.

Diagnosis

Because it is a genetic condition, Kallmann syndrome is present at birth. However, many people don’t receive a diagnosis until puberty is supposed to be in full swing—between ages 14 and 16. 

A doctor will begin by asking questions about certain symptoms (like delayed puberty) and sense of smell. They might also conduct the University of Pennsylvania smell identification test, in which they’ll ask the person to identify 40 different smells. 

Biochemical testing is a critical part of diagnosing Kallmann syndrome. GnRH isn’t directly measurable in the body. Instead, a doctor will measure blood concentrations of hormones like LH, FSH, and sex steroid hormones like testosterone, estrogen, and progesterone.

A doctor can also order magnetic resonance imaging (MRI) to investigate the hypothalamus, the pituitary gland, and the nose to search for reasons that smell and hormone levels may be awry.

Finally, the diagnosis can be confirmed with genetic testing.

Treatment

There are two major goals of Kallmann syndrome treatment—to help induce puberty, and later on, to jump-start fertility. 

Standard treatment for Kallmann syndrome begins with hormone replacement therapy. For males, that often means testosterone treatment. For females, that usually means estrogen and progesterone treatment.

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

The goal of that treatment, at the outset, is to help induce puberty and the development of secondary sexual characteristics. Hormone treatment is also important for maintaining bone density, which can dwindle due to a lack of sex hormones. 

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

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

Testosterone and estrogen/progesterone therapy won't induce fertility on their own. 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 as many as 75%–80% of male patients. Therapies like pulsatile GnRH can also help stimulate ovulation in females. Assisted reproduction therapy is also an option for people with Kallmann syndrome looking to conceive.

Genetic counseling is also a consideration for those with Kallmann syndrome or who have family members with the condition and who want to understand the risk that their children may inherit it.

These treatments can reduce the burden of symptoms. However, they don't cure the underlying genetic causes of the condition.

Prognosis

Kallmann syndrome isn't a life-threatening disease, but it usually lasts a lifetime. 

Treatment can begin once patients receive a diagnosis. But many patients with Kallmann syndrome, and other forms of CHH, often undergo a diagnostic odyssey (an unpredictable journey). In short, it takes time before clinicians 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 symptoms.

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

Later in life, challenges related to Kallmann syndrome often center around fertility. Though many patients are misdiagnosed as sterile, there are well-established treatments that can help restore fertility for both males and females.

Coping

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

One review paper on the psychological aspects of Kallmann syndrome and CHH notes estimated 56% of females and 72% of males with Kallmann syndrome or other forms of CHH are teased due to their condition. Body image concerns (like body shame) were reported in 93% of males and 80% of females with Kallmann syndrome.

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

Improving the emotional experience of Kallmann syndrome begins with an 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 condition present at birth. It results in a reduced or absent sense of smell and delayed or absent puberty. Diagnostic tests include tests for hormones and genetic testing. Hormone treatment can trigger puberty and improve fertility.

A Word From Verywell

Getting a Kallmann syndrome diagnosis is emotionally challenging—particularly if it is not caught until later adolescence. However, there are well-established treatments that can manage most of the major symptoms and induce fertility. With early diagnosis, treatment, and support from peers and healthcare professionals, people with Kallmann syndrome can thrive.