Unique Genetics Of Legius Syndrome

Overview

Legius syndrome is a disorder that leads to different coloured spots on the skin called café-au-lait patches (French: coffee with milk). Typically this is accompanied by learning and speech difficulties, alongside freckling in the armpit and groin areas. The disorder has similar symptoms to Neurofibromatosis Type 1 (NF1), but unlike NF1, Legius syndrome does not lead to the formation of nerve tumours (neurofibromas).

Consequently, it is necessary to differentially diagnose (i.e. separate) the two conditions through a genetic test. The syndrome can be spontaneous (i.e. occur from nowhere), but it is also a hereditary disorder that can be passed onto babies.¹ If you are planning on having a family and you or your partner currently has Legius syndrome, it may be worth getting a prenatal genetic counselling session to discuss your options. Below, we will discuss the genetics of Legius syndrome, its inheritance, and the treatment options and future outlook of the disease. 

What does ‘genetics’ actually mean?

When doctors refer to ‘genetics,’ they are referring to the information that all humans (and animals) have. This genetic information derives from deoxyribonucleic acid, more well-known collectively as DNA.² Our DNA is packaged into structures called chromosomes, and in humans, there are 46 chromosomes in total.

These are generally grouped into pairs (i.e. 23 paired chromosomes) as we receive one pair from each parent.² Out of the 23 paired chromosomes, 22 are called autosomal, while the 23^rd pair are called the sex chromosomes due to their nature in determining a person’s sex. Chromosomes have distinct patterns called bands³, and within these bands are hundreds to thousands of genes.²

Genes contain information for enzymes in our body to create proteins that are used in other biochemical reactions.² Consequently, dysfunctional genes can lead to reduced protein production, or a total lack of their formation causing serious detrimental effects. All this genetic information is found in every cell of our body. 

Genetic mutations and diseases

Due to the paired nature of our chromosomes, we generally receive two copies of a gene. In other words, we receive one copy per chromosome. If a gene is dysfunctional, this will usually lead to the onset of disease. Depending on the gene, one dysfunctional copy may be enough to cause disease (dominant), while others require both copies to cause disease (recessive).⁴ Mutations of a gene can lead to a gene’s dysfunctionality, but otherwise, mutations may just lead to a variation in a physical trait, and not necessarily disease.⁵ 

Mutations can be caused by different types of mutagens, which can be classed into either physical or chemical mutagens. Examples of some mutagens include ultraviolet (UV) radiation or benzene.⁶ The human body has different biological pathways that help in repairing or counteracting damage caused by these mutagens, but depending on the nature of the damage, cannot fully stop the onset of disease.

Mutations can also be inherited (i.e. from parents to offspring), more descriptively known as germline mutations. Germline mutations are not necessarily indicative of disorders, but depending on the type of gene mutation that is inherited, can also lead to disease.⁷ 

Inheritance

As genes can have different variations, the term ‘alleles’ is used for the different versions of a gene. Humans have two alleles, where each pair represents a gene’s functionality. As mentioned previously, the inheritance of a particular trait or disorder can be dominant or recessive. Depending on the type of chromosome affected, it will have different names. For disorders that affect the autosomal chromosomes, inheritance can either be in an ‘autosomal dominant,’ or ‘autosomal recessive’ fashion.

A genotype can be used to define the allele variation through a simple letter assignment. For example, let us define a healthy allele with the capitalised H and an unhealthy allele with a lowercase h. The following possible genotypes then are as follows:

• HH
• Hh or hH
• hh

The resulting genotype can give rise to a physical trait, i.e. a phenotype. Following our definitions, let us say that the disorder is autosomal recessive, this means we need two copies of the allele, ‘h,’ in order to cause disease. Using the definitions above, let us combine the genotypes and the following phenotypes:

There are multiple ways to calculate the probability of a disease occurring by using our knowledge of how a gene is inherited. A common way to show inheritance is through the use of a tabular chart, also known as a Punnett square. Using the same letter definitions above, let us form a more specific chart of how the alleles are inherited when both parents are carriers (Hh).

Using the Punnett square above, we can then calculate that out of four possible children, 25% of the time, the child will be diseased. Fifty percent (50%) of the time, the child will carry the disease. In another 25% of the time, the child will be healthy. 

The genetics of Legius syndrome

Inheritance of Legius syndrome

Legius syndrome is a disorder that has an autosomal dominant inheritance pattern. This means that only one copy of the gene is needed to cause disease. For example, let us now define capital S as the diseased allele copy and lowercase s as the healthy copy. These are the possible genotypes and phenotypes:

As visualised in the table above, there are no carriers. This is due to one copy of the gene being enough to cause disease. Punnett squares are visualised below showcasing the probabilities of offspring being diseased given the parents’ phenotypes. Please note that the probability of an individual having two copies of the diseased allele (SS) has not been reported, since that would mean that both parents would have had to have Legius syndrome, which is unlikely.

Additionally, as there is a lack of literature on any individuals with two copies of the disease, this may indicate that embryos that have the genotype of (SS) from parents who both have (Ss), pass away before birth. Consequently, only two punnett squares are shown below showing (Ss x ss) and (Ss x Ss).

To reiterate, an individual having two copies of the diseased allele (SS) has not been reported,¹ and two individuals with the disease (Ss) are unlikely to have children together. Therefore, the most probable chance for a baby to have Legius syndrome would most likely be 50%,¹ given that a parent with Legius syndrome has a partner who does not have the disease.¹ 

Gene involved

Legius syndrome specifically involves the mutation of the gene SPRED1.⁸ This gene is responsible for controlling the level of signalling between cells. Cellular signalling is a major function that helps the body know when to keep producing more cells.⁸

SPRED1 is particularly involved in the inhibition (activity reduction) of a particular pathway called the RAF-RAS pathway.⁹ The RAF-RAS pathway is responsible for the proliferation (production) of cells and thus can lead to an overgrowth of cells.⁹ Skin cells such as melanocytes which produce melanin, can over-proliferate and thus can cause discoloration (the café-au-lait spots) as seen in Legius syndrome.¹⁰ Despite the mutation in SPRED1, the gene is not totally dysfunctional, although the proteins the gene produces are heavily shortened or truncated.^2,8

Mutations in the gene that happen spontaneously are also possible, and can also cause Legius syndrome. In a clinical trial of 23 families, six individuals were diagnosed with Legius syndrome despite no family history.²

Diagnosis and treatment

Genetic screening & other symptoms

Most children diagnosed with Legius syndrome will have a parent who also has the syndrome (Nerve Tumour UK). If no family history is found, molecular genetic testing can be used. Molecular testing involves a blood test followed by next generation sequencing (NGS).² NGS then allows scientists to compare an individual's gene versus an average gene (reference gene).¹¹ Any abnormalities between the individual’s gene and the reference can then be used to diagnose Legius syndrome. Other symptoms that can be used to diagnose Legius syndrome may include developmental delays or ADHD-like traits.² These are not present in all cases, however. The mechanism for how SPRED1 may cause developmental delays is not known. Although symptoms are quite similar to NF1, differences include the lack of tumours, which can therefore allow doctors to more easily distinguish the difference between the two.

Treatment

Patients with ADHD-like symptoms can be treated with some medicine, while those with developmental delays or speech delays can be given therapy or possible education plans.² The future outlook for patients with Legius syndrome is good, and there are no studies that indicate a shortened lifespan. 

Summary

Legius syndrome is a disorder that causes café-au-lait patches to occur on the body. It can be caused spontaneously (new mutations) or it can be inherited from either parent. Inheritance of Legius syndrome is in an autosomal dominant fashion, which means only one copy of the mutated gene is enough to cause the disease.

Specifically, the mutation of the SPRED1 gene causes the disease which leads to the overproliferation of cells. This is due to the SPRED1 gene not producing full proteins that are used to inhibit the RAF-RAS pathway. Patients and children with the syndrome can live full lives and have therapies available for them to have a more fulfilling life.