Overview

Legius syndrome, or neurofibromatosis type 1-like syndrome, is a very rare genetic disorder with a prevalence of 1 in 46,000 to 75,000 births.¹ Although Legius syndrome has always existed, due to its great similarity to neurofibromatosis type 1, for many years, it used to be categorised, and diagnosed, as neurofibromatosis. It wasn’t until 2007 that researchers distinguished this medical condition from neurofibromatosis and gave it recognition as a separate syndrome on its own, with distinct characteristics.² 

This disorder is characterised by multiple light-brown or café-au-lait spots. Café-au-lait spots are changes in skin pigmentation, forming flat patches on the skin, that are different in colour, compared to their surrounding areas. Other signs and symptoms of this disorder include, frecklings on the skin, abnormally large head (macrocephaly), learning difficulties, attention deficit hyperactivity disorder (ADHD), and developmental delays. Due to this disorder being a rather recent disease, there’s still research being done on it.¹ 

There are many unknowns about this disorder. It is still being researched and studied extensively. Although so much attention has been given to its physical characteristics, there’s still little research and findings on the cognitive impact of this syndrome on the individual. Current knowledge of this disease is based on a small sample of very few individuals because not a great number of individuals have been identified with this disease yet. However, a better understanding of this disease and its signs and symptoms will become available once more and more individuals are identified with Legius syndrome.² 

This article will concentrate on the cognitive impact Legius syndrome can cause by exploring intellectual abilities, executive function, and quality of life. 

What is Legius syndrome?

Legius syndrome is an inherited genetic condition. This disorder is caused by a genetic mutation in the SPRED1 gene of the human genome. The SPRED1 gene is responsible for the production of the Spred1 protein, which inhibits an important cell signalling pathway. This cellular signalling pathway controls crucial cellular functions such as, an increase in the number of cells and cell growth (proliferation), specialisation of cells, so they can carry specific functions (differentiation), cell movement and self-destruction of cells (apoptosis). A mutation in this gene results in overactivation of this cellular signalling pathway and deregulation of normal cellular functions.^1,2 

The symptoms observed most in Legius syndrome are after café-au-lait spots (discolorations on the skin):² 

• Skin foldings and frecklings in unusual areas such as the groin, armpits and under the breasts
• Non-cancerous lumps of fat or lipomas
• Abnormally large head or macrocephaly
• Unusual facial features such as eyes that are widely apart
• Learning disabilities
• Attention deficit disorder (ADD)
• Attention deficit hyperactivity disorder (ADHD)
• Developmental delays

What are cognitive functions?

To understand cognitive functions, it is important first to define cognition, which is the ability to obtain knowledge through the senses, thinking, and experiencing. Thus, cognitive functions are the tools that we use to acquire knowledge, some of them are language, memory, judgment, perception, planning, decision-making, reasoning, and others that require complex intellectual processes. A cognitive deficit occurs when one or more of the cognitive functions have an impairment. Cognitive deficits can be a consequence of many conditions.³

Cognitive functions in Legius syndrome

Neurobehavioural and developmental problems are two of the most observed clinical manifestations of Legius syndrome. Patients with Legius syndrome have variable degrees of cognitive impairment, ranging from no impairment to severe impairment. It is possible that an individual with a confirmed case of Legius syndrome shows no symptoms of cognitive impairment.^2,4,5 

In 2009, researchers, studied a group of 42 individuals with confirmed mutation of the SPRED1 gene; meaning patients with Legius syndrome. They learned that from the 42 individuals, three individuals had ADHD and two individuals had ADD. Also, developmental delays such as speech and/or language delays were observed in six individuals.⁴ In another study done in 2011 , intelligence and behaviour in 15 patients with Legius syndrome were investigated. Data collected in this study showed that the group of children with Legius syndrome had a lower score of full-scale IQ, compared to those without Legius syndrome, but this difference wasn’t significant.⁵ 

On the other hand, the performance IQ score, in children with Legius syndrome, was significantly lower than the performance IQ score of the family members without Legius syndrome. This study also discovered motor delay in five children with Legius syndrome, speech delay in five children and ADHD in three children.² Research that was done on groups of children with Legius syndrome, by few other researchers,  has reported learning disabilities as a cognitive impact of Legius syndrome.^2,6,7,8,9 

Overall, from the research done so far on Legius syndrome, it has been discovered that common cognitive impairments associated with this disorder are difficulties with attention, processing speed, working memory, speech and movement. These studies have several limitations. In order to have a more clear understanding of this disorder with more accurate data, a larger group of affected individuals need to be evaluated using more comprehensive neuropsychological testing.⁵ 

Understanding the clinical manifestations, and their respective diagnosis and treatment, can help the individual, family and the healthcare team to prepare a better treatment plan for the individual affected with Legius syndrome. However, it is important to consider that these findings are lacking detailed descriptions, and are only gathered from a small sample size.²

How are these cognitive impairments diagnosed?

In order to do so, after initial diagnosis of Legius syndrome, patients can undergo a clinical evaluation to assess the severity of their symptoms. This clinical evaluation includes a developmental assessment, neuropsychiatric evaluation and genetic testing.^2,5,9 

How are these cognitive impairments treated? 

There is no cure for Legius syndrome. The only treatment is clinical monitoring and management of the symptoms associated with this disease. For example, while Legius syndrome itself can not be changed, the symptoms such as developmental delays, and neurobehavioural problems, can be managed to facilitate and improve the quality of life of the patients with this condition.²

Summary 

Currently, to diagnose the Legius syndrome, is a challenge. For many years, this syndrome was considered part of neurofibromatosis, therefore, the research and the analysis of the cases are very recent. There are not many cases studied, making it difficult to have a completely established set of symptoms. In the specific case of the cognitive impact, due to this data being based on a very small group of individuals (with less than 30 persons),  a need for larger and more accurate studies on cognitive impact of Legius syndrome is indicated.