Legius syndrome

Legius syndrome is a rare autosomal dominant genetic condition caused by pathogenic variants in one copy of the gene SPRED1. It 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 (milder than typically seen with NF1); and
• lipomas.

In contrast to NF1, children with Legius syndrome do not present with neurofibroma, Lisch nodules or central nervous system tumours.

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 that is unable to bind to RAF, meaning that the RAS/MAPK pathway is continuously active.

SPRED1 pathogenic variants are loss of function and a range of nonsense, frameshift, missense (in critical regions), splice-site, in-frame deletions, and copy number changes (such as whole or partial gene deletions) have been reported.

There is no recognised genotype:phenotype correlation and no known founder variants.

Legius syndrome may be diagnosed if at least two of the following criteria are present:

• five or more café-au-lait macules bilaterally distributed and no other NF1-related diagnostic criteria, except for axillary or inguinal freckling;
• an identified constitutional (germline) heterozygous pathogenic (or likely pathogenic) variant in SPRED1; and/or
• a parent diagnosed with Legius syndrome according to the above criteria.

For information about how to access testing for the SPRED1 gene, see Child with multiple café-au-lait macules.

• Legius syndrome is inherited in an autosomal dominant pattern. Individuals affected by an autosomal dominant condition have one working copy of the gene, and one with a pathogenic variant.
• The chance of a child inheriting the gene with the variant from an affected parent is 1 in 2 (50%).
• 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.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

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.

Note that the current list of known clinical characteristics 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: Allied condition – Legius syndrome