Legius syndrome is a genetic condition, first described in 2007, that is often confused with the more common Neurofibromatosis Type 1 (NF1). It is classified as an autosomal dominant disorder, meaning a person needs to inherit only one copy of the altered gene. Characterized primarily by changes in skin pigmentation, the syndrome was initially designated as NF1-like syndrome. Accurate diagnosis and management are important due to its clinical overlap with other disorders.
Defining Legius Syndrome and its Genetic Basis
Legius syndrome is a neurocutaneous disorder and is one of the RASopathies, conditions caused by dysregulation of the RAS signaling pathway. The condition is caused by a pathogenic variant in the SPRED1 gene, located on chromosome 15. This gene provides instructions for making the Spred-1 protein, which normally acts as a negative regulator of the RAS-mitogen-activated protein kinase (RAS-MAPK) signal transduction cascade.
A mutation in the SPRED1 gene typically results in a nonfunctional or shortened protein that cannot perform this regulatory role effectively. This loss of inhibition leads to an overactive RAS signaling pathway, which drives the characteristic features of Legius syndrome. Since it is inherited in an autosomal dominant pattern, a child has a 50% chance of inheriting the condition if one parent is affected.
Clinical Manifestations
The most consistent clinical feature of Legius syndrome is the presence of multiple café-au-lait macules (CALMs), which are flat, light-brown spots darker than the surrounding skin. Nearly all individuals with the syndrome develop these pigmentary lesions, and their number often increases throughout childhood. These spots are often one of the earliest signs of the condition, sometimes visible by the time a child is one year old.
Another common pigmentary sign is the presence of freckling in the skin folds, particularly in the armpit (axillary) and groin (inguinal) regions. Beyond skin changes, patients may also present with non-cutaneous features, including an abnormally large head circumference, known as macrocephaly. Developmental and cognitive issues are also frequently reported, such as mild learning difficulties, developmental delays, and behavioral challenges like Attention-Deficit/Hyperactivity Disorder (ADHD).
Distinguishing Features from Neurofibromatosis Type 1
Legius syndrome was initially difficult to distinguish from Neurofibromatosis Type 1 (NF1) because both conditions are characterized by multiple café-au-lait macules and skin fold freckling. Up to 50% of individuals with Legius syndrome may fulfill the clinical diagnostic criteria for NF1 based on these pigmentary features alone. This clinical similarity stems from the fact that both the SPRED1 gene and the NF1 gene code for proteins that regulate the same RAS signaling pathway.
The two conditions are genetically distinct, with NF1 resulting from a mutation in the NF1 gene. The defining difference is the systemic absence of the more severe, tumor-related hallmarks of NF1 in Legius syndrome patients. Individuals with Legius syndrome typically do not develop neurofibromas (benign nerve sheath tumors characteristic of NF1) or Lisch nodules (hamartomas found in the iris of the eye). Furthermore, Legius syndrome does not involve the optic pathway gliomas or the specific bone abnormalities often seen in NF1, leading to a generally milder prognosis.
Diagnosis and Ongoing Management
The diagnosis of Legius syndrome requires clinical suspicion and confirmation through genetic testing. Because the symptoms overlap significantly with NF1, especially in young children, a definitive diagnosis is difficult to make based on physical examination alone. Physicians will suspect Legius syndrome in individuals who have the pigmentary changes of multiple café-au-lait macules and freckling but lack the tumor or bone features of NF1.
Molecular genetic testing is the only way to confirm the condition by identifying a pathogenic variant in the SPRED1 gene. This testing typically involves sequence analysis of the SPRED1 gene to detect small changes, and sometimes deletion/duplication analysis for larger genetic alterations.
Once confirmed, the management of Legius syndrome is primarily supportive, focusing on the specific symptoms of the individual. Regular developmental assessments are necessary to screen for and address any learning difficulties, developmental delays, or behavioral issues. Treatment may include physical, speech, or occupational therapy, and pharmacological therapy may be considered for managing ADHD.