Highlight HEALTH

The 2008 NF Conference was held last weekend (June 6 — 10) in Bonita Springs, Florida. The preeminent annual meeting provides a forum for basic and clinical neurofibromatosis (NF) investigators to present their research (pronounced noor-oh-fahy-broh-muh-toh-sis). The conference was attended by over 200 researchers from around the world

This year’s theme — Genes to Complications to Treatments — highlighted the progress being made in NF research and clinical care, as well as the research programs of the Children’s Tumor Foundation. Last year’s NF Conference focused on models, mechanisms and therapeutic targets.

The neurofibromatoses are familial cancer syndromes that predispose individuals to the development of a variety of benign and malignant tumors in the central and peripheral nervious systems. The disorders cause tumors to grow along various types of nerves and can also affect the development of bones and skin. Neurofibromatosis has been classified into three distinct types:

• Neurofibromatosis type 1 (NF1) occurs in 1:3,500 births and is caused by a mutation of the NF1 gene on chromosome 17q11.2. NF1 diagnostic criteria (two or more) include cafe-au-lait macules, freckling, optic glioma, Lisch nodules, bony abnormalities, a first-degree relative with NF1, two or more benign nerve sheath tumors (neurofibromas) of any type, or at least one plexiform neurofibroma [1-2].
  At least 95% of NF1 patients develop benign tumors called neurofibromas [3], which may be disfiguring or associated with pain and neurological defect. As there is no cure for neurofibromatosis, the only therapy is surgical removal of the tumor and associated nerve. Approximately 6 — 13% of NF1 patients will progress and develop a malignant peripheral nerve sheath tumor (MPNST), an aggressive sarcoma that has a high mortality rate (~ 50%) [4].

• Neurofibromatosis type 2 (NF2) occurs in 1:25,000 births and is caused by a mutation of the NF2 gene on chromosome 22q12. Ninety percent of NF2 patients develop bilateral vestibular schwannomas and/or spinal schwannomas. Enlarging schwannomas can compress adjacent structures, resulting in deafness or other neurologic deficits depending on their location. Surgical removal of these tumors is difficult, often resulting in patient morbidity. Although 95% of schwannomas occur sporadically, multiple schwannomas are the hallmark of inherited NF2 [5].

• Schwannomatosis occurs in 1:40,000 patients and, in contrast to NF2, develop multiple peripheral schwannomas, but not schwannomas of the vestibular nerve. Schwannomas in schwannomatosis patients are often associated with severe, intractable neuropathic pain and sometimes numbness, tingling and weakness. It was believed that a germline mutation in an unidentified gene predisposes patients to NF2 mutation [6]. Recently, the INI1 gene was identified as a possible schwannomatosis gene [7-8].

Both NF1 and NF2 are tumor suppressor genes.

The Children’s Tumor Foundation (CTF) is dedicated to ending neurofibromatosis through research. The CTF has funded NF research for over 25 years with the goal of identifying NF drug therapies and improving the lives of those living with the disorder. The Foundation also endeavors to increase public awareness of NF and provides resources for NF patients and their families.

For more information on NF, visit the Children’s Tumor Foundation and Neurofibromatosis Cafe.

CTF medical podcasts are also available.

References

1. Riccardi VM. The prenatal diagnosis of NF-1 and NF-2. J Dermatol. 1992 Nov;19(11):885-91.
   View abstract
2. Gutmann et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA. 1997 Jul 2;278(1):51-7.
   View abstract
3. Rasmussen and Friedman. NF1 gene and neurofibromatosis 1. Am J Epidemiol. 2000 Jan 1;151(1):33-40.
   View abstract
4. Evans et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002 May;39(5):311-4.
   View abstract
5. Evans et al. A genetic study of type 2 neurofibromatosis in the United Kingdom. I. Prevalence, mutation rate, fitness, and confirmation of maternal transmission effect on severity. J Med Genet. 1992 Dec;29(12):841-6.
   View abstract
6. Jacoby et al. Molecular analysis of the NF2 tumor-suppressor gene in schwannomatosis. Am J Hum Genet. 1997 Dec;61(6):1293-302.
   View abstract
7. Hulsebos et al. Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am J Hum Genet. 2007 Apr;80(4):805-10. Epub 2007 Feb 16.
   View abstract
8. Hadfield et al. Molecular characterisation of SMARCB1 and NF2 in familial and sporadic schwannomatosis. J Med Genet. 2008 Jun;45(6):332-9. Epub 2008 Feb 19.
   View abstract

The annual Children’s Tumor Foundation NF Conference was held in Park City, Utah earlier this week (June 10 — 12). For three days, research and clinical investigators from around the world met to present their data and discuss the latest findings in neurofibromatosis (NF) research (pronounced noor-oh-fahy-broh-muh-toh-sis). This year the meeting focused on models, mechanisms and therapeutic targets.

The Children’s Tumor Foundation is dedicated to ending NF through research. The Foundation has sponsored research for over 25 years to understand the molecular basis of NF and to establish effective treatments and improve the lives of those living with the disease.

What is neurofibromatosis (NF)?

NF is usually inherited as an autosomal dominant genetic disorder of the nervous system that causes clinically benign tumors to form on peripheral and optic nerves. However, 30-50% of NF cases arise as a result of a spontaneous genetic change. Tumors that develop in individuals with NF can cause disfigurement, deafness, blindness, bone deformation, learning disabilities and death. NF is the most common neurological disorder caused by a single gene and affects more than 100,000 Americans, making it more prevalent than cystic fibrosis, hereditary muscular dystrophy, Huntington’s disease and Tay-Sachs disease combined [1].

There are two genetically distinct forms of NF: type 1 (NF1), also known as von Recklinghausen NF, which occurs in 1:3,500 births and type 2 (NF2), also known as bilateral acoustic NF, which is rarer than NF1, occurring in 1:25,000 births. A third distinct type of NF, schwannomatosis, has only recently been recognized and affects 1:40,000 individuals. Both NF1 (neurofibromin 1) and NF2 (neurofibromin 2) genes are tumor suppressors.

Symptoms of NF often appear at birth and usually by 10 years of age. Cutaneous neurofibromas (meaning tumors that develop on or just under the skin) typically start to develop around puberty and the number of these tumors increase with age. Although approximately 95% of type 1 neurofibromas are clinically benign, patients often require surgical removal because of disfigurement or disability [2]. However, depending on tumor location, surgery may not be an option and currently, there are no successful molecular therapies.

The most common tumor in individuals with NF1 is the benign peripheral nerve sheath tumor or neurofibroma. In 5-10% of children, a subtype of benign neurofibroma, plexiform neurofibroma, can undergo malignant transformation and become a malignant peripheral nerve sheath tumor (MPNST), a highly aggressive cancer with poor survival [2]. In addition, 15-20% of children with NF1 develop low-grade astrocytomas, typically involving the optic pathway, which may result in vision loss or abnormal endocrine function if they invade the hypothalamus [3].

Clinical advances in NF are being propelled by two recent initiatives:

• NF clinical drug trials are being conducted by a new consortium of ten major teaching hospitals called the NF Clinical Trials Consortium and holds the promise of accelerated drug development.
• The Children’s Tumor Foundation NF Clinic Network, established as a pilot program of four clinics in 2006, is now being rolled out nationwide to provide optimal care at the local level. Components of the network include standards of treatment, clinic operating guidelines and a patient database. Future plans include a centralized tissue repository to facilitate the identification of NF biomarkers and to help identify new drug targets.

Despite these advances, federal funding for research and clinical trials for NF has decreased sharply and is facing the threat of greater cutbacks. The Congressionally Directed Medical Research Program’s NF Research Program has decreased 2.5-fold over the last two years from $25 million in 2005 to $10 million in 2007 [4].

I encourage readers to visit the Children’s Tumor Foundation and consider a gift donation to make a difference in the lives of those affected by NF.

References

1. Facts & Statistics. Children’s Tumor Foundation.
2. Friedman and Birch. Type 1 neurofibromatosis: a descriptive analysis of the disorder in 1,728 patients. Am J Med Genet. 1997 May 16;70(2):138-43.
   View abstract
3. Arun and Gutmann. Recent advances in neurofibromatosis type 1. Curr Opin Neurol. 2004 Apr;17(2):101-5.
   View abstract
4. On the cusp of major clinical advancements, funding for neurofibromatosis research may dry up. Children’s Tumor Foundation press release. 2007 Apr 23.