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NF1 or Legius Syndrome? – An Emerging Challenge of Clinical Diagnosis

Recently a new NF1-like but genetically distinct disorder, caused by mutations in the gene SPRED-1, was identified.  The disorder has been termed Legius Syndrome after Dr. Eric Legius, the University of Leuven, Belgium-based clinician researcher who first created a mouse model of SPRED-1 mutations and then began characterizing patients with the disorder. Individuals with Legius Syndrome have some recognizable NF1-like features: café-au-lait spots, axillary freckling and macrocephaly (large head size). However these persons do not develop the neural tumors or long bone dysplasias that are commonly seen and can be devastating in NF1.

Because the features of Legius Syndrome overlap with NF1, what has challenged physicians is how to integrate this new information into day-to-day diagnosis and management of patients who at first glance might appear to have NF1. This is an important consideration because Legius Syndrome seems to be overall a milder disorder than NF1. As a result individuals with Legius Syndrome will most likely have a less unpredictable and less severe outlook than NF1, and therefore something that is important to communicate to the patient and family as soon as possible.

To get a handle on differential diagnosis of the two disorders, a team led by Dr. Legius and University of Alabama-based Dr. Ludwine Messiaen examined a clinical group of young patients diagnosed as first case in their family with Legius Syndrome*. The group also examined over 1300 blood samples from patients seen in the past with a broad range of NF1-like features but no detectable NF1 mutation in the blood. 34 different SPRED-1 mutations were identified in this group.  Of significance, 1.9 percent of individuals with a clinical diagnosis of NF1 would actually be classified to have Legius Syndrome based on genetics. In the clinical group, nearly half of the individuals with a SPRED1 mutation also fulfilled the NF1 diagnostic criteria. Notably, café-au-lait spots and freckling on the skin in young children can’t be differentiated between cases of SPRED-1, and cases of NF1.

The take home message here is that clinical differentiation of NF1 and Legius Syndrome may not be immediately clear, with the clinical differences becoming apparent only over time as the disorders unfold.  However, molecular genetic testing should be able to resolve a diagnosis in most such cases. The team recommends initially looking for an NF1 mutation and, if negative, moving to SPRED1 testing if the patient has café-au lait spots, freckling and no other NF1 diagnostic features. Overall, clinicians including general practitioners, clinical geneticists, pediatricians, ophthalmologists, dermatologists, neurologists, and oncologists, involved in the care, diagnosis, and treatment of individuals with NF1, should be aware that Legius syndrome can resemble NF1.

* Messiaen et al. (2009)Clinical and Mutational Spectrum of Neurofibromatosis Type 1-like Syndrome. JAMA Nov 18: 302 (19): 2111-2118. (See also commentary by Stevenson and Viskochil in the same issue).