Clinical characteristics: Legius syndrome is characterized by multiple café au lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1 (NF1). Additional clinical manifestations reported commonly include intertriginous freckling, lipomas, macrocephaly, and learning disabilities / attention-deficit/hyperactivity disorder (ADHD) / developmental delays. Current knowledge of the natural history of Legius syndrome is based on the clinical manifestations of fewer than 300 individuals with a molecularly confirmed diagnosis; better delineation of the clinical manifestations and natural history of Legius syndrome will likely occur as more affected individuals are identified.
Diagnosis/testing: The diagnosis of Legius syndrome is established in a proband with suggestive findings and a heterozygous pathogenic variant in SPRED1 identified by molecular genetic testing.
Management: Treatment of manifestations: Consideration of behavioral modification and/or pharmacologic therapy for those with ADHD; physical, speech, and occupational therapy for those with identified developmental delays; and individualized education plans for those with learning disorders.
Surveillance: Routine screening for developmental delays and behavioral and learning problems.
Genetic counseling: Legius syndrome is inherited in an autosomal dominant manner. Many affected individuals have an affected parent. Each child of an individual with Legius syndrome has a 50% chance of inheriting the pathogenic variant and developing clinical features of the disorder. Preimplantation genetic testing or prenatal testing for pregnancies at increased risk is possible if the SPRED1 pathogenic variant has been identified in an affected family member.
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