Kallmann syndrome occurs in people of both genders. However, it is more common for men to seek medical advice and intervention when signs of puberty fail to appear. Thus, more cases of Kallmann syndrome have been recorded in men; about 1 in 30,000 males as opposed to about 1 in 120,000 females have been diagnosed with Kallmann syndrome, about 4 times as many men. While this rare disease usually causes symptoms that are life-long, about 10-15% of individuals with Kallmann syndrome have experienced spontaneous recovery of normal hormone levels during their lifetime. 

Kallmann syndrome is caused by a lack of gonadotropin-releasing hormone (GnRH), produced and released by specialized cells in the brain known as GnRH neurons. The development of GnRH neurons originates in the developing nose, and these cells migrate along the nasal passages involved in developing sense of smell, finally reaching the hypothalamus to be activated during puberty. Mutations in the development and migration of GnRH neurons is thus linked to development of olfactory neurons that enable a person’s sense of smell, and likely explains why so many individuals with Kallmann syndrome lack a sense of smell (anosmia). This is not always the case; in cases when the GnRH neurons migrate properly but possess mutations that inhibit release of GnRH hormones, the individual will experience Kallmann syndrome but retain their sense of smell. 

Some cases of Kallmann syndrome have been linked to genetic inheritance from the parents, and some present spontaneously without a known genetic cause. Human genes are located on condensed sequences of DNA known as chromosomes. Every person has 23 pairs of chromosomes, one inherited from each parent. Different genes can be located on one or more chromosomes, and every single cell nucleus contains every chromosome. Depending on the cell type, only certain genes within these chromosomes are expressed, meaning that the DNA is transcribed into mRNA that makes the proteins that the cell needs to grow and thrive. A person’s sex-linked characteristic genes are located on the twenty-third pair of chromosomes. In females, both of these chromosomes are the same size known as X chromosomes, while males have one X chromosome and one different Y chromosome. Thus, the Y chromosome can only be inherited from the father. In order to better understand the genetic cause of Kallmann syndrome mutations, a few common inheritance patterns are detailed below:

1. Sex-linked inheritable traits can arise since the mother always provides an X chromosome to the offspring and the father provides either an X or a Y. If the mother carries a mutation on the X chromosome, it can either be compensated by the father’s donated X chromosome with a normal gene (female offspring) or become apparent in offspring if the father donates a Y chromosome (male offspring). 

2. In autosomal dominant inherited disorders, a mutated gene need only be on one chromosome to have an effect on the offspring. This can be inherited from only one parent if they carry the mutated gene.

3. In autosomal recessive inherited disorders, a mutated gene must be present on both paired chromosomes in order to exhibit a trait in the offspring. This means that both parents need to pass on their chromosome with a mutated gene to pass this trait to their children. 

4. Oligogenic inherited disorders come from two or more different mutated genes must interact to cause a disease in the offspring. These genes may each have a mutation, one could have multiple mutations, and they combine in a way that affects the desired protein and its function in the cell. 

5. Still other mutated genes may not come from the parents’ chromosomes, but may occur in offspring spontaneously during development and combination of genetic information. These are known as “de novo” mutations.

There are a number of genes that, when mutated, can lead to a lack of proper migration of GnRH neurons to the hypothalamus or, alternatively, affect the GnRH neurons’ ability to produce and release GnRH hormone. Genetic mutations that cause Kallmann syndrome associated with lack of smell (anosmia) impede GnRH cell migration during fetal development. These include Kal1, NELF, FGFR1, PROKR2, HS6ST1, CHD7, WDR11, SEMA3A. Alternatively, genes that do not affect GnRH cell migration but prevent release of GnRH hormone from these cells cause Kallmann syndrome without losing sense of smell. These genetic mutations include KISS1R, TACR3, GNRHR. Some genes can cause Kallmann syndrome with and without anosmia depending on the case: FGFR1, PROKR2, HS6ST1, CHD7, WDR11, SEMA3A. More details about the chromosome location, inheritance pattern, mutated protein, and resulting KS and/or anosmia symptoms are detailed in the table.

The primary symptoms experienced by individuals with Kallmann syndrome are a lack of hormones leading to fewer or no developments during puberty. Many individuals also experience lack of smell (anosmia) as detailed in the causes section due to the migratory pattern of the hormone releasing cells GnRH neurons. While both males and females are diagnosed with Kallman syndrome, their symptoms will present themselves in slightly different ways at puberty. Males diagnosed with Kallmann syndrome may have testicles that did not descend, decreased bone density and muscle mass leading to decline in growth, lack of penile growth (micropenis), erectile dysfuntion, low sex drive, and infertility. Females diagnosed with Kallmann syndrome will likely not start their menstrual period, have little to no development of breast tissue, and experience a similar lack of body hair and growth to their male counterparts. Some individuals may also experience symptoms such as facial abnormalities affecting the nose (anosmia), mouth (cleft palate), and eyes (abnormal movement or blindness), kidney problems (development of only one kidney), shortened fingers and/or toes, hearing loss, or color blindness. These latter symptoms are more rare, as symptoms generally present themselves at the onset of puberty. 

Many individuals diagnosed with Kallmann syndrome begin seeking medical advice or genetic counseling at or around puberty when they fail to exhibit common developmental characteristics. In males, this diagnosis may occur earlier if the testicles fail to descend or due to a smaller than average penis. Thus, Kallmann syndrome is 4 times more likely to be diagnosed in males than in females. 

Diagnostic tests for Kallmann syndrome focus primarily on determining the cause that the individual is not experiencing the characteristics of sexual development at puberty. There are a number of ways that individuals are evaluated:

1. Physical examination - a doctor may examine the individual to for common developmental characteristics of puberty; failure to discern proper milestones may prompt further investigation 

2. Tanner staging – method used by endocrinologists to evaluate proper maturation of primary and secondary sexual characteristics during puberty

3. Hormonal evaluation – the hormones released by the hypothalamus and pituitary glands circulate in the blood and are delivered to the reproductive organs. Blood tests can measure levels of LH and FSH hormones compared to normal levels at puberty. The levels of sex hormones released as a result, testosterone and estrogen, can also be measured at diagnosis. GnRH is generally not measured, only the hormones released as a result of this signal are.

4. Olfactory testing - the nasal cavity may be scanned by MRI to determine if lack of smell (anosmia) is due to Kallmann syndrome or physical blockage in the nasal cavity

5. Genetic testing to confirm inheritance and subtype of KS: There are genetic tests available for mutations in KAL1,GNRHR, KISS1R, FGFR1, PROKR2, CHD7, and TACR3 genes are available to confirm the diagnosis. (http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab?db=GeneTests)

The primary treatment offered to individuals with Kallmann syndrome is the replacement or supplement of growth hormones that induce development of reproductive organs. Due to the lack of GnRH release, males may have decreased testosterone levels and females may have decreased estrogen levels. Hormone replacement therapy can be administered to induce sexual development. In males, testosterone is administered to signal the testes to produce sperm. In females, estrogen and progesterone are administered to signal to the ovaries to produce and release eggs to induce menstruation. This hormone supplementation must be tailored to the individual’s needs and adjusted after the onset of puberty for maintenance of growth and reproductive characteristics. 

Individuals with Kallmann syndrome should consider genetic and/or family counseling to seek advice from medical professionals about how to conceive despite a lack of reproductive signaling hormones. For individuals experiencing infertility as a result of Kallmann syndrome, pituitary hormones LH or FSH or even synthetic GnRH can be administered to increase fertility. Additionally, normal levels of hormones circulating in the bloodstream are associated with maintaining healthy bone density. Individuals with Kallmann syndrome may receive treatment for possible loss of bone density to avoid future complications such as osteoporosis.

Kallmann syndrome, while a life-long disease, is not life threatening and is treatable. Individuals with Kallmann syndrome experience delayed or lack of onset of puberty due to failure to release GnRH hormone. Hormone replacement therapy tailored to each individual’s needs can induce puberty and even reverse infertility, enabling the individual to reproduce normally. As therapy continues, different levels of hormones may need to be administered to meet the needs of the individual. If self-administered, such as in the case of testosterone or estrogen replacement, the individual may be able to work with their physician to determine which dose is appropriate. In the cases of LH and FSH replacement therapies or GnRH synthetic supplementation, individuals may need to regularly visit a clinic to receive injections. If left untreated, Kallmann syndrome prevents completion of puberty and causes infertility.

Genetic testing and counseling is available for many genetic disorders, including Kallmann syndrome: http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab?db=GeneTests

1. https://rarediseases.info.nih.gov/diseases/10771/kallmann-syndrome 

2. https://rarediseases.org/rare-diseases/kallmann-syndrome/

3. https://www.rch.org.au/kidsinfo/fact_sheets/Kallmann_syndrome_an_overview/#:~:text=The%20condition%20is%20five%20times,with%20anosmia%2C%20or%20hypogonadotropic%20hypogonadism.

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5. Dodé, C., Levilliers, J., Dupont, JM. et al. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet 33, 463–465 (2003). https://doi.org/10.1038/ng1122

6. Legouis, R. et al. The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules. Cell 67, (1991).

7. Dodé, C. et al. Kallmann syndrome: Mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet. 2, (2006).