Definition

Legius syndrome (OMIM #611431) is a genetic disease caused by mutations in the SPRED1 gene. Clinically, it is predominantly characterized by multiple café au lait spots without the occurrence of other manifestations of neurofibromatosis type 1 (NF1).

Key Data

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Previous synonym Neurofibromatosis type1-like syndrome (NFLS)
Gene SPRED1
Gene product SPRED1
Function Part of the RAS/MAPK signaling pathway
Heredity Autosomal dominant
Prevalence Unknown, although approximately 2% of patients who meet the NF1 diagnostic criteria have a SPRED1 mutation (the prevalence of NF1 is 1:3000).
Genotype-phenotype correlation Unknown
Penetrance Nearly all patients exhibit café au lait spots and intertriginous freckling.
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Diagnosis

Suspected Diagnosis

Legius syndrome is suspected when the following findings apply:

  • Café au lait spots with or without intertriginous freckling
    AND

  • The absence of other clinical manifestations of NF1 (e.g. Lisch nodules, neurofibromas, optic glioma, sphenoid bone dysplasia, dysplasia of the long bones)
    AND

  • A parent with multiple café au lait spots without other signs of NF1

Genetic Diagnostics

The diagnosis of “Legius syndrome” is confirmed by the detection of a heterozygous germline mutation in the SPRED1 gene. Initially, a sequence analysis of SPRED1 should therefore be performed. If this does not reveal a mutation, a deletion/duplication analysis should follow. It may be helpful to use panel examinations consisting of multiple genes.

Differential Diagnoses

  • Neurofibromatosis type 1

  • Noonan syndrome

  • Autosomal-dominant, inherited café au lait spots

  • Other diseases associated with café au lait spots

Clinical Presentation

Legius syndrome is very similar to NF1 with regard to dermal manifestations. Nearly all patients exhibit multiple café au lait spots, and many patients also have intertriginous flecking in the region of the armpit and/or groin. Other clinical features of NF1 are absent from Legius syndrome, however.

In a few patients with Legius syndrome, psychomotor developmental delays are described as learning disabilities, particularly affecting speech. ADHD has also been reported as part of the disease. Overall, however, patients with Legius syndrome appear to be less restricted cognitively than patients with NF1.

In addition, a few patients also exhibit vascular changes, described as hemangiomas or vascular malformations.

In individual cases, leukemia is reported in connection with Legius syndrome. Since SPRED1 is part of the RAS/MAPK signaling pathway, an increased risk of neoplasia is suspected when there are mutations in this gene. Due to the limited number of patients with the disease, it has not yet been possible to verify this assumption.

Therapeutic Considerations

Physical or speech therapy can be performed in order to treat any developmental delays. In patients with ADHD, behavioral therapy or drug therapy may be worth considering. If there is a learning disability, individualized educational approaches may be helpful.

Surveillance Recommendations

Surveillance Recommendations

Examinations to determine any developmental delays, changes in behavior, and learning disability should be conducted on a regular basis.

Clinical examinations with blood pressure measurement should continue to be conducted on a regular basis to check for a vascular abnormality.

Patients should be made aware of their potentially increased risk of neoplasia. Specific cancer surveillance is not recommended.

Additional Information

Open Clinical Trials / Registries

There are currently no open clinical trials/registries for patients with Legius syndrome that we can recommend to you for more information.

Support Groups

Unfortunately, we are as yet unaware of any existing support groups for patients with Legius syndrome. We will add new information as it becomes available.