Legius Syndrome Often Mistaken for Neurofibromatosis Type 1

Allison Gandey

November 18, 2009

November 18, 2009 (UPDATED November 19, 2009) — It has a new name and should not be mistaken for neurofibromatosis type 1, researchers say. The pigmentary signs often fool clinicians, but investigators explain that Legius syndrome is genetically distinct and caused by mutations in the SPRED1 gene.

Neurologists should be aware that Legius syndrome can resemble neurofibromatosis type 1, Ludwine Messiaen, PhD, from the University of Alabama at Birmingham, told Medscape Neurology. "It is important to make the correct diagnosis as the course of both diseases is significantly different, with Legius syndrome being generally associated with a milder clinical phenotype," she said.

Neurologists should be aware that Legius syndrome can resemble neurofibromatosis type 1, report investigators led by Ludwine Messiaen, PhD, from the University of Alabama at Birmingham.

In patients with café au lait macules, neurofibromatosis should be analyzed first and, if negative, SPRED1 testing considered (photo by Andreas Werle).

It is a message they want all clinicians involved in the care, diagnosis, and treatment of patients with neurofibromatosis to understand. General practitioners, clinical geneticists, pediatricians, ophthalmologists, dermatologists, and oncologists will all need to comprehend the differences between the two.

The group's work appears in the November 18 issue of the Journal of the American Medical Association.

Diagnostic criteria for neurofibromatosis were established by the National Institutes of Health. Neurofibromatosis type 1 is an autosomal dominant disorder that affects approximately 1 in 3000 individuals worldwide. It is characterized by multiple café au lait macules, skin-fold freckling, and tumors of the nervous system. Other frequently observed features are bone abnormalities, short stature, an abnormally large head, and learning problems.

Legius syndrome is a genetically distinct but similar disorder. It is characterized mainly by café au lait macules, axillary freckling, and macrocephaly.

Dr. Messiaen and colleagues point out that although a diagnosis may become apparent over time, it can be uncertain for individuals who do not develop multiple signs. The researchers note that molecular genetic testing will resolve the diagnosis in most cases.

Testing for SPRED1 Mutations

"We recommend that neurofibromatosis should be analyzed first and, if negative, SPRED1 testing should be considered in patients with café au lait macules with or without freckling and no other diagnostic features," write the researchers.

Dr. Ludwine Messiaen

They suggest that a SPRED1 mutation may relieve a psychological burden from families who otherwise would be waiting for potential serious neurofibromatosis-associated manifestations.

"Legius syndrome typically follows a more benign course and clinical management should primarily focus on developmental and speech delays, learning disabilities, and attention deficit and hyperactivity disorder," Dr. Messiaen said.

To determine the frequency, mutational spectrum, and phenotype of Legius syndrome, the team conducted a cross-sectional study. They evaluated 23 unrelated patients with a SPRED1 mutation and their families.

Investigators also used samples from a second cross-sectional study of more than 1300 unrelated, anonymous patients. They had a broad range of signs typically found in neurofibromatosis type 1 but no detectable germline mutation. Investigators tested these samples for SPRED1 mutations.

Researchers found that among 42 SPRED1-positive individuals from the clinical cohort, just less than half fulfilled National Institutes of Health neurofibromatosis diagnostic criteria (48%; 95% confidence interval, 32% – 64%). Patients had more than 5 café au lait macules with or without freckling or a family history of neurofibromatosis.

None of the 42 SPRED1-positive individuals had discrete cutaneous or plexiform neurofibromas, osseous lesions, or symptomatic optic pathway gliomas, report investigators.

In the anonymous cohort, researchers identified 34 different SPRED1 mutations, 27 pathogenic mutations, and 7 probable nonpathogenic missense mutations.

Of the 94 probands with familial café au lait macules with or without freckling and no other features, 73% had a neurofibromatosis type 1 mutation, and another 19% had a SPRED1 mutation. In the anonymous cohort, 1.9% of patients with the clinical diagnosis of neurofibromatosis type 1 actually had Legius syndrome.


"A correct diagnosis has important implications for prognosis, counseling, and potential prenatal genetic diagnosis," note investigators.

In another study published in the July issue of the Journal of Medical Genetics, investigators screened 85 patients for SPRED1 mutations. They identified 6 cases of Legius syndrome (2009;46:431–437).

Lead investigator Gillian Spurlock, PhD, from Cardiff University in the United Kingdom, and her team came to a similar conclusion and suggest that identification of SPRED1 mutations has important implications for counseling families.

Coauthor Raymon Vijzelaar, MSc, is a scientist employed by MRC-Holland, a provider of commercially available multiplex ligation-dependent probe amplification assays.

JAMA. 2009;302:2111–2118.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.