Kallmann syndrome is a rare genetic disorder that causes a delay or a complete absence of puberty.
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Kallmann syndrome is a rare genetic disorder that causes a delay or a complete absence of puberty. In males, it’s caused by low testosterone levels due to problems with an important neuroendocrine gland in the brain called the hypothalamus.
People with this condition also either have an impaired sense of smell or a complete inability to smell. There is another form of the condition that doesn’t cause problems with smell. Together, these disorders are called congenital hypogonadotropic hypogonadism.
Like many medical conditions, Kallmann syndrome is named after the person who discovered it. The German-American geneticist Franz Kallmann first described three families with Kallmann syndrome in the1940s.
Most people with Kallmann syndrome find out they have it during adolescence due to problems with puberty that prompt a visit to the doctor. The prevalence of Kallmann syndrome is thought to be about 1 in 48,000 people, including 1 in 30,000 males and 1 in 125,000 females.
The main sign of Kallmann syndrome is a complete lack of puberty or delayed puberty. Disrupted puberty is caused by abnormally low levels of the sex hormone testosterone in males due to problems with the hypothalamus in the brain.
Some boys may see a complete lack of puberty, while others have some of the features of normal development.
Puberty usually occurs in males between the ages of 9 and 14. Changes that occur during this time include:
Sudden growth spurt
Deepening voice
Facial and body hair growth
Pubic hair development
Increased muscle mass
Enlargement of testes and penis
Acne
Increased sweat and body odor
More frequent sexual thoughts and erections
Children with Kallmann syndrome may not experience these characteristic sex changes during puberty. Compared to their peers, people with this condition may have issues such as:
Lack of pubic hair
Kallmann syndrome isn’t the only cause of delayed puberty, and differentiating it from other conditions generally requires many different tests, such as blood tests to measure hormone levels. Doctors are most likely to suspect Kallmann syndrome if you also have trouble smelling.
People with Kallmann syndrome may have anosmia (the complete inability to smell) or hyposmia (a partial inability to smell).
Compared to people without Kallmann syndrome, boys with this condition also seem to have higher rates of other developmental differences. The following non-gonadal problems may occur:
Micropenis, which might be identified at birth
Cryptorchidism (undescended testicles)
Cleft lip and cleft palate
Color blindness
Renal agenesis, or being born with only one kidney
Brain impairment
Hearing loss
Trouble with eye movement
Abnormal hand movements (synkinesis)
Poor muscle control (cerebral ataxia)
Seizures
Breast development in males
Disproportionately long arms compared to height
Short fingers
Kallmann syndrome is caused by genetic mutations. Sometimes these mutations are inherited from your parents. Other times, they develop without a family history or any other known underlying cause.
The biggest risk factor for Kallmann syndrome is your sex. Males are affected about four times more often than females.
Multiple genetic patterns of inheritance have been identified in people with Kallmann syndrome, including:
Autosomal dominant. Dominant inheritance means you only need to receive an associated mutation from one parent to develop a certain condition. Almost two-thirds of cases of Kallmann syndrome linked to a family history are inherited this way.
Autosomal recessive. Recessive inheritance means you need to receive an associated gene from both parents to develop a certain medical condition. It’s the second most common form of inheritance in people with Kallmann syndrome.
X-linked recessive. X-linked inheritance means the causal gene mutation is passed through families on one X chromosome. Males have one of these chromosomes, and females have two. Because males don’t have a backup copy, they’re more likely to develop genetic conditions due to problems with this chromosome. X-linked variants are the least common inheritance pattern for Kallmann syndrome.
Many children with Kallmann syndrome are diagnosed in adolescence when they fail to reach normal puberty milestones. Parents may notice their children haven’t developed the same characteristic signs of puberty that their peers have, such as a deeper voice or body hair.
Puberty can develop at different times, so noticing your child is a late developer isn’t necessarily a cause for concern. But it’s still a good idea to take your child to see their pediatrician if you’re worried they may be dealing with a hormonal problem.
Your child’s provider may initially perform tests such as:
Asking you and your child about their symptoms
Performing a physical exam to look for any abnormalities
Reviewing their personal and family medical history
If your doctor suspects your child may have a hormonal problem, they may send them to a pediatric endocrinologist for further testing. This is a doctor who specializes in hormonal problems in children.
Further tests they may receive include:
Blood tests to measure hormone levels, particularly testosterone levels, LH levels, GnRH levels, and FSH levels
GnRH stimulation test to see if the pituitary gland responds to GnRH
Brain MRI to look for abnormalities in structures such as the pituitary gland or hypoplasia of the olfactory bulbs
Genetic testing to look for associated mutations
Smelling tests
Managing Kallmann syndrome usually requires regular visits with a specialist in endocrinology.
Kallmann syndrome doesn’t have a cure. Treatment usually comes in the form of hormone replacement therapies to aid sexual development. For males, this usually means testosterone replacement therapy to raise testosterone levels into a normal range.
Administering testosterone to males is usually successful at triggering puberty. Testosterone can be administered in various ways, including:
Injections
Creams
Patches
Gels
Implantable pellets
Lifelong hormone replacement therapy is needed to keep testosterone levels in a healthy range. Doctors usually recommend starting hormone therapy around the age of 12 with low-dose testosterone and then increasing the dose over 12 to 24 months to replicate puberty.
For adult men, long-term pulsatile GnRH therapy is administered to treat infertility because GnRH stimulates the release of FSH, which is needed for proper sperm development.
This treatment usually involves receiving GnRH under the skin every 2 hours for several months to maintain hormone levels. Pulsed GnRH therapy seems to be more effective than another treatment option called human chorionic gonadotropin therapy.
Kallmann syndrome is a genetic condition, and there’s no known way to prevent it. If you suspect your child is not undergoing normal puberty, it’s important to take them to see their healthcare provider for testing. They may refer your child to an endocrine specialist if they suspect a hormonal problem.
You can maximize your child’s outlook by following their doctor’s treatment instructions and attending all their scheduled follow-ups. While living with the condition can be challenging, with appropriate treatment and support, people with Kallmann syndrome can and do lead full and healthy lives.
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It’s not clear exactly what causes Kallmann syndrome. We know it’s a genetic condition present from birth, even though many people don’t realize they have it until puberty. However, the exact gene mutations that contribute to the development of Kallmann syndrome are only partially understood.
Some genetic conditions, like sickle cell anemia and cystic fibrosis, result from a single gene mutation that’s easy to identify. But Kallmann syndrome isn’t one of these conditions. Instead, it seems to be related to a complex interaction between many different genes.
Kallmann syndrome fits more broadly into a group of conditions classified as hypogonadotropic hypogonadism, meaning low sex hormones (testosterone in males) due to problems with the hypothalamus or pituitary gland.
About 40 genes have been associated with the development of hypogonadotropic hypogonadism.
The most common genetic mutations seen in people with Kallmann syndrome are in the KAL1 and FGFR1 genes. However, doctors can’t find any evidence of genetic mutations associated with the condition in about 35 to 45 percent of people.
Other genes that seem to also play a role include PROK2, FGF8, and PROKR2.
People with Kallmann syndrome develop issues with puberty due to low levels of sex hormones. The primary sex hormone is testosterone in men and estrogen and women.
In people with Kallmann syndrome, abnormal testosterone levels are caused by differences in the development of the hypothalamus before birth. Your hypothalamus is often called the “master gland” because it controls the levels of other hormones in your body.
Kallmann syndrome occurs when the development and/or migration of GnRH neurons in the fetus is disrupted. GnRH neurons are a special group of nerve cells that stimulate the release of the hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from your pituitary gland.
Kallmann syndrome also causes problems with your ability to smell due to abnormal development of your olfactory nerves.
LH acts on your testicles, causing them to produce testosterone. FSH plays an important role in stimulating the production of sperm. Low levels of LH in people with Kallmann syndrome due to GnRH deficiency lead to low testosterone.
Surges in testosterone normally kick off puberty. But it’s delayed in people with Kallmann syndrome due to low levels of this essential hormone.
In women, delayed puberty is caused by low estrogen production by the ovaries. Disruptions of estrogen in females can cause many problems, including with ovulation and fertility.
Idiopathic simply means there is no known cause for a certain condition. So, idiopathic hypogonadotropic hypogonadism is when you have low levels of GnRH, but doctors can’t determine why. People with this variant have similar signs and symptoms as people with Kallmann syndrome, but they don’t have issues with their sense of smell. Normal smelling ability is medically known as normosmia.