Legius syndrome

Legius syndrome (LS) is an autosomal dominant condition characterized by cafe au lait spots.^[3] It was first described in 2007 and is often mistaken for neurofibromatosis type I. It is caused by mutations in the SPRED1 gene.^[5][6] It is also known as neurofibromatosis type 1-like syndrome.^[1]

Legius syndrome
Other names	Neurofibromatosis 1-like syndrome[1]
This condition is inherited in an autosomal dominant manner.
Symptoms	café au lait spots; +/- learning disabilities[2]
Usual onset	at birth
Causes	Mutations in the SPRED1 gene[3]
Diagnostic method	Clinical findings, Genetic test[4]
Differential diagnosis	neurofibromatosis type I
Treatment	Physical therapy, Speech therapy[2][1]
Prognosis	good
Frequency	rare (estimated at 1:46,000-1:75,000)[2]

Symptoms and signs

See also: List of conditions associated with café au lait macules

larger café au lait spot on right forearm

Nearly all individuals with Legius syndrome show multiple café au lait spots on their skin.^[7] Symptoms may include:^[2]

• 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.^[1]

Cause

CHR 15

Legius syndrome is a phakomatosis^[8] and a RASopathy, a developmental syndrome due to germline mutations in genes.^[7][9] 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).^[10][11] The gene in question demonstrates almost 100 mutations.^[1]

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.^[2][12]

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.^[4][1][13]

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.^[2]

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.^{[medical citation needed]}

Treatment

Management of Legius syndrome is done via the following:^[2][1]

• Physical therapy
• Speech therapy
• Pharmacologic therapy (e.g. methylphenidate for attention deficit hyperactivity disorder)^[14]

The prognosis of this condition is generally considered good with appropriate treatment.^{[citation needed]}

See also

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