What is Legius syndrome?

Legius syndrome is a disease caused by mutations – or genetic changes – in the SPRED1 gene. Due to the numerous café au lait spots on the skin (benign, light-brown, uniform pigment spots), it bears a clinical resemblance to neurofibromatosis type 1 (NF1). The other NF1 manifestations however do not occur.

How is Legius syndrome diagnosed?

Suspected Diagnosis

Legius syndrome is suspected with the following presentations:

  • Café au lait spots with or without intertriginous freckling (resembling freckles in the region of the armpit or groin)

  • A lack of other clinical manifestations of NF1, such as Lisch nodules (small, brownish-white to yellow, sharply defined spots in the iris of the eye), neurofibromas (nerve tumors), optic glioma (benign nerve tumor of the optic nerve), or certain bone changes (sphenoid bone dysplasia, dysplasia of the long bones)

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

Genetic Diagnostics

The diagnosis of “Legius syndrome” is confirmed by detection of a mutation – or genetic change – in the SPRED1 gene.

What is the risk of cancer?

In some isolated cases, Legius syndrome has been associated with leukemia. It is known that various defects or changes in a specific signaling pathway (RAS/MAPK signaling pathway) inside our body’s cells result in an increased risk of developing cancer. The mutation responsible for Legius syndrome also affects this signaling pathway, which suggests that there is an increased risk of malignant diseases. Due to the low number of patients, however, it has not yet been possible to confirm this assumption.

Legius syndrome is very similar to NF1 with regard to manifestations of the skin. Nearly all patients exhibit numerous café au lait spots, and many patients also have intertriginous freckling in the armpit and/or groin region. The additional clinical features of NF1 are however lacking in the case of Legius syndrome.
In a few patients with Legius syndrome, psychomotor developmental delays are described as a learning disability, specifically 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.

What causes Legius syndrome?

Legius syndrome is caused by mutations – or genetic changes – in the SPRED1 gene. These genes encode for a protein (SPRED1) of the RAS/MAPK signaling pathway, which transmits information in our cells.

Now if the SPRED1 gene is altered, the corresponding protein will not be produced correctly and will no longer be able to perform its normal function. This then results in a faulty transfer of information within the cell, which can lead to skin changes and developmental delays, among other things.

The incidence of the disease is not yet known; however, around 2% of patients that meet the NF1 diagnostic criteria, have an SPRED1 mutation. The incidence of NF1 is 1:3000. Legius syndrome can be passed on by parents to their children, as an autosomal dominant disease.

Is there a treatment?

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 learning plans may be helpful.

Surveillance Recommendations for the Early Detection of Cancer

Surveillance Recommendations

Examinations to determine any developmental delay, 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 informed about their potentially increased risk of cancer. Specific cancer surveillance is not recommended.

Self-Care and Support

What should I pay special attention to?

You should consult a doctor as soon as anomalies in learning behavior, developmental changes, or other behavioral changes occur in your child. Non-specific symptoms such as fatigue or a feeling of weakness should also be noted and reported to a doctor. You should likewise go to a doctor if new anomalies or complaints develop.

Support Groups and Additional Information

Unfortunately, we are as yet unaware of any existing support groups for patients with Legius syndrome. We will add any new information in this regard as soon as we learn of it.