Legius syndrome

Legius syndrome is a rare genetic condition that should be considered in the differential of a child presenting with multiple café-au-lait macules, but without neurofibromas or other tumour manifestations of neurofibromatosis type 1 (NF1).

The key presenting feature of Legius syndrome is multiple café-au-lait macules without neurofibroma formation.

Additional features that may be reported include:

• axillary and/or inguinal freckling;
• macrocephaly;
• learning difficulties/ADHD; and
• lipomas.

Legius syndrome is caused by pathogenic variants in the SPRED1 gene, a negative regulator of the RAS/MAPK signalling pathway involved in cell growth, differentiation and apoptosis. The normally functioning SPRED1 protein will block RAF-induced RAS/MAPK signalling. Pathogenic variants in the SPRED1 gene typically lead to a shortened protein which is unable to bind to RAF, meaning that the RAS/MAPK pathway is continuously active.

For information about testing, see Presentation: Child with multiple café-au-lait macules.

Legius syndrome is an autosomal dominant condition, meaning an individual is affected when there is a pathogenic variant in only one of the two copies of the SPRED1 gene. Many patients with Legius syndrome have an affected parent.

An individual with the condition has a 50% (1-in-2) chance of passing on the SPRED1 pathogenic gene change to each child. While penetrance (clinical manifestations of the condition) is thought to be close to 100%, the age at which café-au-lait macules appear, and their number, is variable.

A multidisciplinary team approach for clinical manifestations, including assessment and intervention for any suspected developmental delay, learning difficulties or behavioural manifestation, is recommended in the treatment and surveillance of patients with Legius syndrome. Suggested approaches are published by several authors.

The clinical characteristics of Legius syndrome that are currently known is based upon a relatively small cohort of patients (less than 300). Management of Legius syndrome may therefore evolve over time as more information becomes available.

For clinicians:

• GeneReviews: Legius syndrome
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory
• US National Library of Medicine: ClinicalTrials.gov database

References:

• Legius E, Messiaen L, Wolkenstein P and others. ‘Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: An international consensus recommendation‘. Genetics in Medicine 2021: volume 23, issue 8, pages 1,506–1,513. DOI: 10.1038/s41436-021-01170-5

For patients:

• Nerve Tumours UK: Legius syndrome