What are the other Names for this Condition? (Also known as/Synonyms)

• Neurofibromatosis Type 1 Like Syndrome
• NF1-Like Syndrome

What is Legius Syndrome? (Definition/Background Information)

• Legius Syndrome, also known as NF1-Like Syndrome, is a rare, genetic skin pigmentation disorder characterized by multiple café-au-lait macules with or without axillary or inguinal freckling
• The clinical presentation of Legius Syndrome is very similar to that of neurofibromatosis type 1 (NF1)
• Patients typically present with multiple café-au-lait spots sometimes associated with intertriginous freckling, but lack Lisch nodules, optic pathway gliomas, bone abnormalities, neurofibromas or other tumor manifestations
• The number of café-au-lait macules tends to increase with age during childhood
• Other less common manifestations include short stature, macrocephaly, Noonan-like facies, pectus excavatum/carinatum, lipomas, hypopigmented macules, vascular lesions, learning disabilities, attention deficit/hyperactivity disorder (ADHD), and developmental delay

(Source: Legius Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Who gets Legius Syndrome? (Age and Sex Distribution)

• Legius Syndrome is a rare congenital disorder. Less than 200 cases have been currently reported in the medical literature
• The presentation of symptoms can occur in the neonatal phase, infancy, or childhood
• Both men and women may get affected

What are the Risk Factors for Legius Syndrome? (Predisposing Factors)

• A positive family history may be an important risk factor, since Legius Syndrome is an inherited condition
• Currently, no other risk factors have been clearly identified for Legius Syndrome

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Legius Syndrome? (Etiology)

• Legius Syndrome is caused by mutations in the SPRED1 gene, which is involved in regulation of the RAS-MAPK signal transduction pathway
• The RAS-MAPK pathway is a signal transduction pathway that regulates cell cycle and proliferation
• The condition is inherited in an autosomal dominant manner

Autosomal dominant inheritance: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

What are the Signs and Symptoms of Legius Syndrome?

The signs and symptoms of Legius Syndrome may include:

• Attention-deficit hyperactivity disorder (ADHD)
• Axillary freckling
• Cafe-au-lait spot 
• Downslanted palpebral fissures
• Epicanthus
• Generalized hypotonia
• High, narrow palate
• Hypertelorism
• Low posterior hairline
• Low-set, posteriorly rotated ears 
• Macrocephaly
• Micrognathia 
• Multiple lipomas   
• Neurofibromas   
• Ptosis
• Short neck
• Specific learning disability 
• Triangular face

Based on the frequency of symptoms observed, the following information may be noted.

Occasionally present symptoms in 5-29% of the cases: Abnormality of the sternum

(Source: Legius Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Legius Syndrome Diagnosed?

Legius Syndrome is diagnosed on the basis of the following tests and procedures:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms
• Laboratory tests
• Imaging studies
• Biopsy studies, if necessary
• Differential diagnosis to rule out conditions that may present with signs and symptoms similar to Legius Syndrome 
• Molecular genetic testing to check for or confirm causative gene mutation(s)

What are the possible Complications of Legius Syndrome?

The complications of Legius Syndrome may include:

• Severe learning disabilities and behavioral issues
• Low self-esteem and depression

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Legius Syndrome Treated?

There is no cure for Legius Syndrome, since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complication that develops. The treatment methods may include:

• Medication for ADHD
• Physical therapy to improve muscle tone
• Speech and occupational therapy
• Special education for those with learning disabilities

How can Legius Syndrome be Prevented?

Currently, Legius Syndrome may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy. A pre-requisite for prenatal testing is that the causative gene mutation within the family be known/identified
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended

What is the Prognosis of Legius Syndrome? (Outcomes/Resolutions)

• The prognosis of Legius Syndrome is dependent upon the severity of the signs and symptoms and associated complications, if any
• Generally, the prognosis of Legius Syndrome is reported to be good

Additional and Relevant Useful Information for Legius Syndrome:

• About 50% of patients with Legius syndrome fulfill the diagnostic criteria for neurofibromatosis type 1 (NF1), but they have a far milder phenotype compared to NF1 patients
• Legius Syndrome is differentiated from NF1 by the absence of the non-pigmentary clinical manifestations seen in this disorder (i.e., Lisch nodules, neurofibromas, optic glioma, bone abnormalities, etc.)

(Source: Legius Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/