Legius syndrome

Legius syndrome (LS) is an autosomal dominant condition characterized by cafe au lait spots. It was first described in 2007 and is often mistaken for neurofibromatosis type I (NF-1). It is caused by mutations in the SPRED1 gene. It is also known as neurofibromatosis type 1-like syndrome (NFLS). The condition is a RASopathy, a group of developmental syndromes due to germline mutations in genes.

Symptoms and signs

Nearly all individuals show multiple café au lait spots. Features common in neurofibromatosis – Lisch nodules, bone abnormalities, neurofibromas, optic pathway gliomas and malignant peripheral nerve sheath tumors – are absent in this condition. Symptoms, however, may include:

• Freckles
• Lipomas
• Macrocephaly
• Learning disabilities
• ADHD
• Developmental delay

Cause

CHR 15

Legius syndrome 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

In terms of the mechanism of Legius syndrome, the Ras-MAPK signaling, which is a chain of proteins in a cell that sends signals to the nucleus of a cell from the surface receptors, can be regulated adversely by SPRED1 protein. When SPRED1 is dysfunctional then this in turn affects the aforementioned pathway, which in turn eventually leads to the physical symptoms created by this condition.

Diagnosis

Neurofibromatosis-1 has neurofibromas; Legius syndrome does not.

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

Between this condition and NF-1 an important difference is the absence of tumor growths (Lisch nodules and neurofibromas which are common in NF-1) in LS. The symptoms of Legius syndrome and NF-1 are very similar; this is the reason why the two are easily confused. A genetic test is often the only way to make sure a person has LS and not NF-1; 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

Methylphenidate

The prognosis of this condition is generally considered good with the appropriate treatment. Management of Legius syndrome is done via the following:

• Physical therapy
• Speech therapy
• Pharmacologic therapy (e.g. methylphenidate for ADHD)

See also

• List of cutaneous conditions
• List of genes mutated in cutaneous conditions

Further reading

• Review

External links

• PubMed

Classification	ICD-10: Q85.0 OMIM: 611431 MeSH: C548032 DiseasesDB: 34916
External resources	GeneReviews: Legius Syndrome Orphanet: 137605