ja_mageia

Last year saw the emergence of Legius Syndrome, a new NF1-like disorder associated with mutations in the gene Spred-1 on Chromosome 15 (the Nf1 gene is on Chromosome 17).  The name was given to this new disorder by consensus of the NF clinical community at the 2008 European NF Conference in Killarney, Ireland recognizing that this was a fundamental discovery made by Dr. Eric Legius (Catholic University of Leuven beginning with his research in the SPRED-1 mouse model and progressing to human studies. Dr. Ludwine Messiaen University of Alabama at Birmingham)presented an update on the genetics of Legius Syndrome. Spred-1 mutations have now been reported by a few independent studies in patients presenting with café au lait spots and learning disabilities but no tumors or other features of NF1 and no mutations in the Nf1 gene. Dr. Messiaen has identified Spred-1 mutations in 34 patient samples from a library of samples from 1318 patients who presented with apparent clinical NF1 but no Nf1 gene mutations. The Spred-1 gene appears to have 3 functional domains and can have a variety of mutations spread across the gene. Almost half the patients with Spred-1 mutations actually meet the NIH clinical diagnostic criteria for NF1, including café au lait spots. A quarter had speech problems; there were occasional cases of pectus excavatum (chest wall deformities sometimes seen in NF1); but no patients had tumors. Interestingly a small percentage of NF1 patients with Nf1 gene mutations also have mutations in the Spred-1 gene and this is particularly seen in families with characteristic café au lait spots, freckling but no other features of NF1.  Dr. Meena Uphadyaya (Cardiff University) followed Dr. Messiaen’s presentation with parallel data on a UK population study on 110 patients with clinical NF1 but no Nf1 gene mutations; 8% had Spred-1 mutations. Future unraveling of Legius Syndrome will be very important particularly with regards to genetic counseling. Though Legius Syndrome may appear clinically to be like NF1, it looks as though Legius Syndrome will have a far more reduced spectrum of manifestations in the long term than NF1.

Dr. Eric Legius (Catholic University of Leuven) provided an update on his own continuing studies of Spred-1 and particularly the impact of these mutations on cognitive function.  In a small study of 9 children with Spred-1 mutations he saw speech difficulties, ADHD, learning disabilities, and pectus excavatum. Most cases are inherited, with a few being sporadic (first in family) cases. Dr. Legius also continues work on his mouse model of SPRED-1 where his observations of this disorder began. Like Nf1 +/- genetic mouse models the Spred-1 +/- mice have learning disabilities. Dr. Legius did a small study treating these mice with Lovastatin, which corrects learning deficits in Nf1 +/- mice and is now in NF1 clinical trials to treat NF1 learning disabilities. However the drug had no effect in the Spred-1 +/- mice. This may signify that the underlying cognitive issues have a different molecular basis than in NF1 or that potentially the deficit is less severe in SPRED-1. 

Legius Syndrome is emerging as a fascinating disorder and we look forward to continued progress in understanding its basis.

A number of sessions focused squarely upon the issues impacting on the diagnosis and clinical management of NF. Dr. Bruce Korf (University of Alabama at Birmingham) reviewed current diagnostic criteria for NF1 and noted that though there is always a drive to reach consensus – agreement – in the community about how NF1 is diagnosed, what we actually need is more data to be accumulated from patients so that we can have a more comprehensive view of the disorder on which to base these criteria.  Dr. John Mulvihill (University of Oklahoma) focused on NF1 in old age and the fact that individuals with NF1 have accelerated mortality, usually with social issues and poor access to care as impacting factors on this.

Dr. Anat Stemmer-Rachamimov (Harvard/MGH) presented results from a working group that took place at the Eurpean NF Meeting in Killarney, Ireland November 2008, to better classify the terminology used to describe neurofibromas, since currently used terminology can be confusing when the same term is being used to describe different things. These tumors should be classified by location, growth pattern (localized, diffuse or plexiform), association with nerve (tumor expands nerve fascicle and goes outside fascicle), and other histological features. She also addressed the concept that dermal tumors are actually offshoot of plexiform neurofibromas. If you will see a diffuse neurofibroma affecting dermal and subcutaneous layers it is important to examine if the tumor has a relationship to a known plexiform.

Dr. Ian McCutcheon (University of Texas M.D. Anderson Cancer Center) addressed the clinical variability of malignant peripheral nerve sheath tumors (MPNST) in NF1. These tumors affect an estimated 10% of individuals with NF1, but are also seen in the general population as sarcomas. These tumors can appear in diverse sites and usually have a poor prognosis. Chemotherapy will often have only a temporary therapeutic effect, and there is a high mortality rate from these tumors. Radical surgery is often used, taking out tissue beyond the tumor boundaries to ensure the tumor will not return.  The MPNSTs seen in NF1 have unique characteristics rendering them different from non-NF1 related MPNSTs, and this will need to be better understood by clinicians as they develop drug treatment strategies. 

Andre Bernards (Harvard/MGH) examined what genetics can help us predict in NF1 manifestations. For example patients with microdeletions are at greater risk of early onset tumors. Ras clearly has a central role in causing NF1, but Dr. Bernards presented the case for investigating new off-pathway drug targets Ret and Alk receptor tyrosine kinases as well as looking at the role of other gene modifiers, suppressors and enhancers.

One session examined the parallels between NF and other disorders with mutations that affect signaling in the Ras pathway such as Noonan’s syndrome.  Michelle Strecker (UCSF) described her clinics ‘Ras Pathway’ approaches to managing these related disorders, as they share many parallels.  Families are followed through life following diagnosis, and close links are held with advocacy group networks such as the Children’s Tumor Foundation to ensure family support is provided. A close interface is in place with research, translational studies and clinical trials, to ensure patients have rapid access to participating in new studies and newly available therapies. Overall there is a focus on the big picture and quality of life for the patient.

Finally, a popular session chaired by Dr. Rosalie Ferner (Guys and St. Thomas’ NHS Trust) and Dr. Kathryn North (Children’s Hospital at Westmead) pitted the United States against the ‘Rest of World’ in a friendly face-off to evaluate and share opinions on ‘clinical cased that taught me something new’.