Legius Syndrome – Definition
L-2-hydroxyglutaric aciduria (OMIM #236792) is a neurometabolic genetic disease caused by mutations in the L2HGDH gene. It is characterized by cerebellar ataxia, psychomotor retardation, epilepsy, and differing levels of severity of macrocephaly.
Synonym:
Neurofibromatosis type1-like syndrome (NFLS)
Gene:
SPRED1
Gene product:
SPRED1
Function:
Part of the RAS/MAPK signaling pathway
Patterns of inheritance:
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.
Legius Syndrome – 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 detecting a heterozygous germline mutation in the SPRED1 gene. Therefore, a sequence analysis of SPRED1 should be performed initially. 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 in dermal manifestations. Nearly all patients exhibit multiple café au lait spots, and many also have intertriginous flecking in the armpit and/or groin region. However, other clinical features of NF1 are absent from Legius syndrome.
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 this gene is mutated. However, due to the limited number of patients with the disease, this assumption has not yet been verified.
Special Features of 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 educational approaches may be helpful.
Diagnosis of Legius Syndrome- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Diagnosis of Legius Syndrome- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Recommendations for Early Detection in Your Patients
Examinations to determine developmental delays, changes in behavior, and learning disabilities should be conducted regularly.
Clinical examinations with blood pressure measurement should continue to be conducted regularly to check for vascular abnormalities.
Patients should be made aware of their potentially increased risk of neoplasia. Specific cancer surveillance is not recommended.
Legius Syndrome – Further 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.
