Legius syndrome

The cardinal feature is the presence of multiple café au lait macules, which appear and increase in number during infancy and early childhood; intertriginous (axillary and inguinal) freckling is commonly observed. Additional manifestations reported in affected individuals include lipomas, macrocephaly, and a neurodevelopmental profile encompassing learning disabilities, attention-deficit/hyperactivity disorder (ADHD), and developmental delays. Cognitive involvement is generally milder than in . Cardiovascular involvement is uncommon and confined to isolated reports of pulmonic valve stenosis, mitral valve prolapse, and paroxysmal atrial tachycardia. Tumour manifestations characteristic of NF1 (neurofibromas, optic pathway glioma, Lisch nodules) are absent in the vast majority of affected individuals, and the overall clinical course is correspondingly milder.

The estimated prevalence is 1/46,000-1/75,000.

Legius syndrome is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% risk of inheriting the SPRED1 pathogenic variant. Many individuals diagnosed with Legius syndrome have an affected parent. The proportion of individuals with Legius syndrome caused by a de novo pathogenic variant is assumed in the range of ~10–25%. Prenatal molecular testing is technically possible once the pathogenic variant in the family has been identified.

Diagnosis is based on the revised international consensus criteria for NF1 and Legius syndrome, which separate the two conditions on the basis of common pigmentary findings but the absence of NF1-specific tumour and ocular features. The diagnosis Legius syndrome is established if at least two diagnostic criteria are met. These are: six or more café au lait macules bilaterally distributed and no other NF1-related diagnostic criteria except for axillary or inguinal freckling; a heterozygous pathogenic (or likely pathogenic) variant in SPRED1, which is being evaluated as one criterion; a parent with the diagnosis of Legius syndrome by the beforementioned criteria. Because the pigmentary phenotype overlaps substantially with neurofibromatosis type 1 in early childhood, molecular confirmation is frequently required to discriminate the two conditions.

Main differential diagnoses include:

• : Lisch nodules, neurofibromas, optic pathway and other brain glioma, choroidal abnormalities, congenital bowing of limbs, pseudarthrosis, sphenoid bone dysplasia; NF1
• Constitutional mismatch repair deficiency: high frequency of childhood malignancies, pilomatricomas; autosomal recessive with parents often consanguineous; MLH1, MSH2, MSH6, PMS2
• Other RASopathies:

: Hypertrophic cardiomyopathy

: lentigines, hypertrophic cardiomyopathy

: Mild-to-severe intellectual disability, skin abnormalities (hyperkeratosis), sparse hair

HRAS-related : Coarse facial features, ulnar deviation of wrist & fingers, cardiac involvement, rhabdomyosarcoma, neuroblastoma, transitional cell carcinoma of bladder

• Establishing the diagnosis: a germline SPRED1 pathogenic variant identified by genetic testing serves as one criterion for diagnosis. The diagnosis of Legius syndrome cannot be established clinically with certainty without identification of a SPRED1 pathogenic variant. Distinguishing Legius syndrome from NF1 is sometimes impossible on the basis of clinical features alone, especially in young children.
• Surveillance and clinical management: molecular diagnosis is supportive to confirm a diagnosis of Legius syndrome and can enable specific and individualised surveillance and clinical management
• Family member testing: predictive and carrier testing of at-risk relatives can be offered once the pathogenic variant in a family has been identified.

• Stevenson D, Legius E. Legius syndrome. 2010 Oct 14 [updated 2025 Dec 4]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: 20945555.
• Legius E, Messiaen L, Wolkenstein P, Pancza P, Avery RA, Berman Y, et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med. 2021;23(8):1506-1513. PMID: .
• Brems H, Chmara M, Sahbatou M, Denayer E, Taniguchi K, Kato R, et al. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat Genet. 2007;39(9):1120-1126. PMID: .
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