Kallmann Syndrome Pathophysiology

Kallmann syndrome is also known as idiopathic hypogonadotropic hypogonadism with anosmia. It is a genetic condition that is caused by mutations in certain genes. Known mutations occur in genes such as ANOS1, FGFR1, PROKR2 or PROK2. Each of these genes plays a role in the development of certain areas of the fetal brain. Mutations in one of these genes account for up to 30% of cases, while the rest are considered to be caused by an unknown gene mutation.

The exact functions of the genes remain unclear. However, they appear to regulate the formation and migration of the olfactory neurons, which later cause the characteristic symptom of the condition, namely, impaired perception of smell. The olfactory lobe of the brain is absent. Additionally, they are also thought to be linked to the reduced production of gonadotropin-releasing hormone (GnRH), a hormone which stimulates the production of sexual hormones during puberty.

ANOS1 Gene Mutation – Kallmann Syndrome 1

Kallmann syndrome 1 is caused by a mutation in the ANOS1 gene, which follows an X-linked recessive inheritance pattern. That is, the ANOS1 gene is located on the X chromosome and therefore transmitted along with it.

In males, inheritance of one ANOS1 gene mutation can cause the condition, as they only have one X chromosome. It manifests in females only when both parents transmit a similarly affected X-chromosome to the offspring, as they have two X chromosomes. For this reason, males are more likely to be affected by Kallmann syndrome 1 than females.

In most cases, only one individual in a family is affected by Kallmann syndrome 1. This pattern of inheritance is described as simplex. Some patients inherit the gene mutation from their mother, who has a single mutation in one X-chromosome in each cell. Fathers are not able to pass on X-linked traits to their sons, so that the characteristic in male patients is inherited from the mother. Kallmann syndrome 1 can also be developed as a result of a spontaneous mutation in the ANOS1 gene, in which it is not inherited from the mother.

FGFR1 Gene Mutation – Kallmann Syndrome 2

Kallmann syndrome 2 is caused by a mutation in the FGFR1 gene, which follows an autosomal dominant inheritance pattern. This means that a single copy of the gene mutation is able to cause the condition.

Patients may inherit the gene mutation from either one of their parents. Alternatively, a spontaneous mutation in the FGFR1 gene may cause the condition, even in individuals with no family history of Kallmann syndrome.

PROKR2 Gene Mutation – Kallmann Syndrome 3

Kallmann syndrome 3 is caused by a mutation in the PROKR2 gene, which follows an autosomal dominant inheritance pattern. This means that one copy of the gene mutation is sufficient to cause the condition.

Patients may inherit the mutation from either of their parents, or a spontaneous mutation in the PROKR2 gene may occur, causing the condition to manifest in individuals with no family history of Kallmann syndrome.

PROK2 Gene Mutation – Kallmann Syndrome 4

Kallmann syndrome 4 is caused by a mutation in the PROK2 gene, which follows an autosomal dominant inheritance pattern. In this instance, one copy of the gene mutation is sufficient to cause the condition.

The gene mutation may be inherited from either parent. A spontaneous mutation in the PROK2 gene can also cause the condition, for individuals with no family history of Kallmann syndrome.

Other Genes

There are many other genes that are known to be involved in the development of the brain, mutations in which may be linked to Kallmann syndrome. These include:

• HS6ST1
• CHD7
• WDR11
• SEMA3A

There are also many patients with Kallmann syndrome that do not possess a known gene mutation. There are believed to be other mutations that can cause these cases, which remain unidentified. Further research is currently being undertaken to help identify these genes.

References

• https://ghr.nlm.nih.gov/condition/kallmann-syndrome#inheritance
• http://rarediseases.org/rare-diseases/kallmann-syndrome/
• http://emedicine.medscape.com/article/122824-overview#a5
• http://www.omim.org/entry/308700
• http://www.hypohh.net/pdffiles/bookpro.pdf

Further Reading

• All Kallmann Syndrome Content
• Kallmann Syndrome
• Kallmann Syndrome Signs and Symptoms
• Kallmann Syndrome Diagnosis
• Kallmann Syndrome Epidemiology

Written by

Yolanda Smith

Yolanda graduated with a Bachelor of Pharmacy at the University of South Australia and has experience working in both Australia and Italy. She is passionate about how medicine, diet and lifestyle affect our health and enjoys helping people understand this. In her spare time she loves to explore the world and learn about new cultures and languages.