Legius syndrome is a condition characterized by changes in skin coloring (pigmentation). Almost all affected individuals have multiple café-au-lait spots, which are flat patches on the skin that are darker than the surrounding area. Another pigmentation change, freckles in the armpits and groin, may occur in some affected individuals.

Other signs and symptoms of Legius syndrome may include an abnormally large head (macrocephaly) and unusual facial characteristics. Although most people with Legius syndrome have normal intelligence, some affected individuals have been diagnosed with learning disabilities, attention-deficit disorder (ADD), or attention-deficit/hyperactivity disorder (ADHD).

Many of the signs and symptoms of Legius syndrome also occur in a similar disorder called neurofibromatosis type 1. It can be difficult to tell the two disorders apart in early childhood. However, the features of the two disorders differ later in life.

Mutations in the SPRED1 gene cause Legius syndrome. The SPRED1 gene provides instructions for making the Spred-1 protein. This protein controls (regulates) an important cell signaling pathway that is involved in the growth and division of cells (proliferation), the process by which cells mature to carry out specific functions (differentiation), cell movement, and the self-destruction of cells (apoptosis). Mutations in the SPRED1 gene lead to a nonfunctional protein that can no longer regulate the pathway, resulting in overactive signaling. It is unclear how mutations in the SPRED1 gene cause the signs and symptoms of Legius syndrome.

Normal Function

The SPRED1 gene provides instructions for making the Spred-1 protein, which helps control (regulate) the Ras/MAPK signaling pathway. The Ras/MAPK pathway is involved in the growth and division of cells (proliferation), the process by which cells mature to carry out specific functions (differentiation), cell movement, and the self-destruction of cells (apoptosis).

The Spred-1 protein attaches (binds) to a protein called Raf, which is part of the Ras/MAPK pathway. The binding of the Spred-1 protein blocks the activation of Raf, stopping the signaling through the remainder of the Ras/MAPK pathway.

Health Conditions Related to Genetic Changes

Legius syndrome

Mutations in the SPRED1 gene cause Legius syndrome, a condition characterized by multiple café-au-lait spots, which are flat patches on the skin that are darker than the surrounding area.

Several mutations have been identified throughout the SPRED1 gene. These mutations lead to a nonfunctional Spred-1 protein, usually because the mutated gene provides instructions for a shortened protein. The nonfunctional Spred-1 protein is unable to bind and block the activation of the Raf protein, which means the Ras/MAPK pathway is continuously active. It is unclear how mutations in the SPRED1 gene cause the signs and symptoms of Legius syndrome.

Other Names for This Gene

• EVH1/Sprouty domain containing protein
• FLJ33903
• hSpred1
• NFLS
• PPP1R147
• SPRE1_HUMAN
• spred-1
• sprouty related, EVH1 domain containing 1
• sprouty-related, EVH1 domain containing 1
• sprouty-related, EVH1 domain-containing protein 1
• suppressor of Ras/MAPK activation

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

The prevalence of Legius syndrome is unknown. Many individuals with this disorder are likely misdiagnosed because the signs and symptoms of Legius syndrome are similar to those of neurofibromatosis type 1.