Legius syndrome

The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.

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 prevalence of Legius syndrome is not known. Fewer than 200 cases have been reported to date. Prevalence may be higher than expected due to misdiagnosis of cases as neurofibromatosis type 1 (NF1, see this term). The incidence of NF1 is reported to be 1/3000, and about 2% of patients fulfilling diagnostic criteria for NF1 are found to have the genetic mutation underlying Legius syndrome (SPRED1).

The clinical presentation of Legius syndrome is very similar to that of 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.

Legius syndrome is caused by heterozygous inactivating mutations in the SPRED1 gene (15q14), involved in regulation of the RAS-MAPK signal transduction pathway. Nearly 100 different mutations in this gene have been identified. The proportion of cases related to de novo mutations is not yet known. No genotype-phenotype correlations have been found.

About 50% of patients with Legius syndrome fulfill the diagnostic criteria for NF1, but they have a far milder phenotype compared to NF1 patients. Diagnosis based solely on the presence of clinical features is difficult, given the overlap with other disorders characterized by multiple café-au-lait spots. The presence of characteristic clinical signs in parents of affected individuals is supportive of diagnosis. However, molecular genetic testing is required to confirm the diagnosis and testing is available on a clinical basis.

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). Correct diagnosis is essential because of the differences in prognosis and long-term monitoring between Legius syndrome and NF1. Other disorders to consider include Noonan syndrome, Noonan syndrome with lentigines (LEOPARD syndrome), and McCune-Albright syndrome (see these terms).

Prenatal diagnosis is possible and requires prior identification of the disease-causing mutation in the family.

Legius syndrome follows an autosomal dominant pattern of inheritance. Genetic counseling should be provided to affected families.

Drug therapy should be considered for the behavioral manifestations of the disorder (ADHD). Physical, speech, and occupational therapy is recommended for those with developmental delay and educational support for those with learning difficulties.

Given the current knowledge of disease manifestations and complications, the prognosis for patients with Legius syndrome is considered to be very good.

Visit the Orphanet disease page for more resources.

Last updated: 7/1/2014

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.