Overview 

Legius syndrome and neurofibromatosis are two genetic conditions which are very similar but have their own unique characteristics. The high extent of similarity between these two conditions makes distinguishing the two very difficult. However, it is crucial to understand the differences between the two conditions clearly to be able to avoid confusion and make a correct diagnosis. A correct diagnosis helps the patient, examiner and medical professional, to have access to and prepare for the right treatment plan. In this case specifically, as treatment for Legius syndrome and Neurofibromatosis is very different, having the correct diagnosis helps avoid unnecessary costs, therapies and possible surgeries, giving the patient and the family peace of mind. Let’s read more about the characteristics, causes, diagnosis and treatment plan of each condition to learn them better. 

Legius syndrome

What is Legius syndrome? 

Legius syndrome is a rare genetic condition characterized by flat patches of discolouration on the skin. These discolourations are light or dark brown in colour, differing from the surrounding skin by being slightly darker. A common word used to describe these flat patches of colour (pigmentation) is café-au-lait spots.¹ These spots can appear at birth or later in life. As the individual grows older, these spots also tend to increase in number.² This disorder was first described by Brems and colleagues in 2007.³

Signs and symptoms

After café-au lait spots, the most common signs and symptoms of this disorder include: 

• Skin freckles on armpits and groin area
• Macrocephaly or abnormally large head
• Learning disabilities and developmental delays
• Attention deficit hyperactivity disorder or ADHD³

Less common signs and symptoms associated with this disorder include: 

• Unusual facial characteristics such as orbital hypertelorism - eyes that are wider apart than usual 
• Short stature or child with a height well below the average height of other children his age³

It is very crucial to note that although these features could be signs of Legius syndrome, not all signs are present in every case of Legius syndrome and not all cases with these signs have Legius syndrome for certain. Additionally, the severity of these symptoms differs from one individual to another. 

Causes

Mutations (changes) in a gene in our cells, called the SPRED1 gene, lead to Legius syndrome. This gene provides instruction for the production of the Spred1 protein in the cell. The role of this protein is to inhibit a cellular signalling pathway called the Ras/ERK pathway.⁴ This signalling pathway controls many important cell functions such as an increase in the number of cells and cell growth (proliferation), a change of cells from unspecialized cells to specialized cells so they can carry specific functions (differentiation), cell movement and self-destruction of cells (apoptosis).¹ These cell functions are essential for the human body to function properly. A mutation in the SPRED1 gene results in the production of non-functional proteins that can no longer inhibit this necessary cellular signalling pathway. Thus, resulting in hyper-activation of this signalling pathway and deregulation of normal cell functions.⁴ 

Although Legius syndrome is caused by variants of the SPRED1 gene, there still isn’t a clear explanation as to how mutations in this gene cause the signs and symptoms of Legius syndrome.¹ To put simply, there is a correlation between the existence of the SPRED1 gene variant and signs of Legius syndrome. However, the causation behind this phenomenon is still unknown. 

Prevalence

Legius syndrome is a very rare condition, with estimates suggesting it affects about 1 in every 46,000 to 75,000 people (0.001% to 0.002%).⁴ 

Diagnosis

Legius syndrome is diagnosed in a person if two out of the three criteria mentioned below are met:

1. Five or more café-au-lait spots
2. A variant of the SPRED1 gene which means there is a mutation in the SPRED1 gene
3. A parent who has Legius syndrome 

In order to make this diagnosis, first a family history evaluation and physical examination is done. Later, if it is needed, genetic testing will be done to further confirm or rule out the presence of Legius syndrome.³ 

Mode of inheritance 

This disease is an autosomal dominant disorder, which means there is a 50% chance for the child of an affected parent to have Legius syndrome, irrespective of the gender of the offspring. 

Treatment 

There is no actual cure or treatment for Legius syndrome itself. However, there are treatments for the signs and symptoms developed by Legius syndrome such as for ADHD, learning disabilities and developmental delays. These treatments include speech pathology, occupational therapy and physical therapy to help improve development and abilities. Other treatments could include medication for ADHD.³ 

Neurofibromatosis

What is neurofibromatosis?

Neurofibromatosis is the name given to a group consisting of three medical conditions characterized by tumours in the nervous system and the skin. Most of these tumours are non-cancerous (benign) with the possibility of becoming cancerous (malignant).⁵ These medical conditions include neurofibromatosis type 1 (NF1) also known as von Recklinghausen disease, neurofibromatosis type 2 (NF2) and Schwannomatosis (SWN).⁶ Neurofibromatosis was first discovered in 1882 by the German pathologist Friedrich Daniel von Recklinghausen. However, it wasn’t until the 20th century that NF1 and NF2 were distinguished from each other and defined as two different disorders.⁷ In the sections below each of the neurofibromatosis types is explained in more depth. 

Signs and symptoms

Neurofibromatosis type 1

Most people with NF1 have mild symptoms, no serious health issues and an average life expectancy.⁵ The most common symptoms and signs of this condition include: 

• Six or more café-au-lait spots >5mm in diameter in children and >15mm in diameter in adults
• Skin freckles on armpits, groin area and other unusual parts of the body
• Bumps of various sizes on or under the skin (neurofibroma) - on the nerve coverings 
• Larger bumps that develop where multiple branches of nerves come together (plexiform neurofibromas)
• Tumor on the optic pathway (optic glioma) - can result in problems with vision
• Growth on the iris of the eye (Lisch nodules) - these are harmless⁸
• Learning difficulties and developmental delays
• Attention deficit hyperactivity disorder or ADHD
• Autism spectrum disorder or ASD

Neurofibromatosis type 2

NF2 is less common than NF1. Most symptoms of NF2 are caused by the development of benign slow-growing tumors on the nerves responsible for hearing and balance.⁹ These tumours are called vestibular schwannomas.¹⁰ The symptoms caused by these vestibular schwannomas are: 

• Gradual hearing loss
• Hearing ringing or buzzing in the ears 
• Problems with balance
• Headaches¹⁰

Additionally, in some cases, tumour growth is found on cranial nerves (nerves inside the brain), spinal nerves (nerves on the spine) and peripheral nerves (nerves that go to arms and legs and other organs).⁷ These tumours are called schwannomas and lead to symptoms such as:

• Vision problems such as cataracts at an early age (tumour along the optical nerve)
• Weakness and numbness in arms and legs¹⁰

Schwannomatosis

This condition is the rarest condition out of all three. Schwannomatosis shows symptoms between the ages of 25 and 30. The signs of SWN are very similar to NF2 with tumours growing on the cranial, spinal and peripheral nerves, leading to symptoms such as chronic pain, numbness, and weakness anywhere on the body.⁷

Causes

NF1

Mutations in the NF1 gene. 

NF2

Mutations in the NF2 gene. 

Schwannomatosis

Mutation in the SMARCB or LZTR1 gene. 

Prevalence

NF1

NF1 is a very common genetic disorder with the prevalence being 1 in every 3500 cases.⁶

NF2

NF2 is less common than NF1, with the prevalence being 1 in every 25000 humans.⁶

Diagnosis

The diagnosis of neurofibromatosis is very similar to the diagnosis procedure of Legius syndrome. For diagnosis of any of the three types of neurofibromatosis, the first step is a physical evaluation in which the medical professional examines the person for physical signs of neurofibromatosis such as frecklings, café-au-lait spots and soft bumps or any tumours. However, since the three types of neurofibromatosis have very similar characteristics, it is difficult to distinguish the three from each other without genetic testing. Therefore, after the family history evaluation and physical examination, genetic testing is done to discover where the genetic mutation is. 

Treatment

Similar to Legius syndrome, there is no cure for neurofibromatosis. However, through clinical monitoring and medical intervention, the symptoms of this disease can be alleviated. 

For example, surgery can be used to remove tumours. Additionally, the drug selumetinib can be prescribed to stop tumour cells from growing.⁷ Also, if hearing loss occurs, hearing aids could be used.⁹ 

Summary: Legius syndrome vs. Neurofibromatosis 

Legius syndrome and neurofibromatosis are both genetic disorders. 

The most common characteristic between the two is flat dark patches on the skin. However, they have many differences. For example, in most cases of Legius syndrome the only symptom is dark patches. However, in neurofibromatosis, the signs could include tumours that cause loss of vision, loss of hearing and loss of movement. Therefore, compared to legius syndrome, symptoms of neurofibromatosis are a lot more severe and more difficult to take care of.

In terms of diagnosis, the two diseases are very similar with both requiring physical examination and genetic testing. However, as mentioned in each section, it is important to find the gene variant to distinguish between Legius syndrome and neurofibromatosis. Although they’re both caused by genetic mutations, these mutations occur in different genes with respect to each disease. 

With respect to prevalence, Legius syndrome is a very rare genetic disorder, while neurofibromatosis is a lot more common. Additionally, both conditions are autosomal dominant. Furthermore, there is no treatment or cure for either condition and it is only possible to monitor and manage the symptoms caused by the disease such as learning disabilities, problems with hearing, problems with vision, headaches, etc. 

It is important to note that as NF1 is more difficult to cope with and requires more preparations and a more intensive treatment plan. It is important to identify the right disease to avoid the stress related to NF1 diagnosis and to start the correct course of treatment early.