Legius syndrome

Symptoms and signs

Nearly all individuals with Legius syndrome show multiple café au lait spots on their skin. Symptoms may include:

• Freckles in the axillary and inguinal skin fold
• Lipomas, developing in adulthood
• Macrocephaly
• Learning disabilities
• Attention deficit hyperactivity disorder
• Developmental delay Features common in neurofibromatosis – like Lisch nodules (iris hamartomas diagnosed on slit lamp exam), bone abnormalities, neurofibromas, optic pathway gliomas and malignant peripheral nerve sheath tumors – are absent in Legius syndrome.

Cause

Legius syndrome is a phakomatosis and a RASopathy, a developmental syndrome due to germline mutations in genes. The condition is autosomal dominant in regards to inheritance and caused by mutations to the SPRED1 gene at chromosome 15, specifically 15q14 (or (GRCh38): 15:38,252,086-38,357,248). The gene in question demonstrates almost 100 mutations.

Mechanism

A mutated SPRED1 protein adversely regulates Ras-MAPK signaling, which is a chain of proteins in a cell that sends signals from the surface of a cell to the nucleus which in turn causes the symptoms of this condition.

Diagnosis

Genetic testing is necessary to identify the syndrome. The DNA test is necessary sometimes, because symptoms may not be sufficient to definitely diagnose this condition.

Differential diagnosis

The symptoms of Legius syndrome and neurofibromatosis type I are very similar; An important difference between Legius syndrome and neurofibromatosis type I is the absence of tumor growths Lisch nodules and neurofibromas which are common in neurofibromatosis type I.

A genetic test is often the only way to make sure a person has Legius syndrome and not neurofibromatosis type I; the similarity of symptoms stem from the fact that the different genes affected in the two syndromes code for proteins that carry out a similar task in the same reaction pathway.

Treatment

Management of Legius syndrome is done via the following:

• Physical therapy
• Speech therapy
• Pharmacologic therapy (e.g. methylphenidate for attention deficit hyperactivity disorder) The prognosis of this condition is generally considered good with appropriate treatment.

References

References

1. [https://medlineplus.gov/genetics/condition/legius-syndrome/ "Legius syndrome"], Genetics Home Reference, [[National Institutes of Health]]
2. [https://medlineplus.gov/genetics/gene/spred1/ "SPRED1"], Genetics Home Reference, [[National Institutes of Health]]
3. [http://www.medscape.com/viewarticle/712643 "Legius Syndrome Often Mistaken for Neurofibromatosis Type 1"], by Allison Gandley, November 18, 2009, [[Medscape]]
4. "OMIM Entry - # 611431 - LEGIUS SYNDROME".
5. RESERVED, INSERM US14 -- ALL RIGHTS. "Orphanet: Legius syndrome".
6. Rosser, Tena. (February 2018). "Neurocutaneous Disorders". Continuum (Minneapolis, Minn.).
7. Tidyman, William. (2009). "The RASopathies: Developmental syndromes of Ras/MAPK pathway dysregulation". Current Opinion in Genetics & Development.
8. "OMIM Entry - * 609291 - SPROUTY-RELATED EVH1 DOMAIN-CONTAINING PROTEIN 1; SPRED1".
9. "Homo sapiens sprouty related EVH1 domain containing 1 (SPRED1), RefSeq - Nucleotide - NCBI".
10. (2006-01-01). "The Ras/Raf/MAPK Pathway". Journal of Thoracic Oncology.
11. "Legius syndrome {{!}} Genetic and Rare Diseases Information Center".
12. "SPRED1 sprouty related EVH1 domain containing 1 - Gene - GTR - NCBI".
13. (1993). "Legius Syndrome". GeneReviews.
14. (2023-03-27). "Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD)". The Cochrane Database of Systematic Reviews.