A new NF2 Phase 2 clinical trial has been announced using Nilotinib, the second generation of Gleevec (which has been used for decades in a variety of other human tumors). This trial will be through the University Health Network, Toronto Western Hospital (UHN TWH), in Toronto Canada. Dr. Abhijit Guha, Professor of Neurosurgery will conduct and is the Primary Investigator of this trial. Dr. Guha studied sporadic and NF2 schwannomas cell lines provided by House Ear Institute (HEI) and found they overexpressed PDGF and c-Kit Receptors, which are inhibited by Gleevec. He then tested Gleevec on these cell lines. It inhibited schwannoma viability, proliferation and growth, as well as induced apoptosis or cell death. He reported these findings in Cancer Research, in 2009.

Novartis has developed Nilotinib, by slightly modifying the structure of Gleevec, to address the problem of tumors which become resistance to Gleevec after a period of treatment. This targeted biologic also offers lower toxicity and increased tissue penetration - thus potentially having even better results with less side effects. To date, Nilotinib only has been given to adults who have developed a resistance to Gleevec with very satisfactory results. There have been no similar studies in children and its potential use in schwannomas has not been tested. This trial will consist of 45 adult patients with growing vestibular schwannomas, i.e., as seen in serial MRIs showing volumetric growth greater than 15%. Nilotinib is an oral drug, and in the trial will be taken twice a day. The cohort will include both sporadic and NF2 patients. The drug will be administered for 12 months, with follow up for another two years.

The key exclusions will be vestibular schwannomas which due to compression of the brainstem or hydrocephalus is already causing symptoms such as ataxia and headache. The objectives are to determine if the drug can stabilize the growth of the vestibular schwannomas or cause shrinkage of the tumors as defined by 20% or more reduction by MRI volumetric measurement. In addition to tumor growth, other parameters related to hearing, quality of life will also be measured and compared to historical and concurrent patient groups who are managed with current standard treatment strategies which include observation, surgery or radiosurgery.

It is Dr. Guha’s intention to also track other NF2 associated tumors, such as meningiomas and other schwannomas during the trial. A pediatric Phase 1 dose escalation trial is planned for the near future through Hospital for Sick Children, the largest pediatric hospital in Canada. They are using a consortium of hospitals throughout Canada to recruit patients, the majority of whom will have NF2. While Dr. Guha is excited about the potential of this drug, he, like many others, believes NF2 may have to be treated with a combination of current reatment strategies (surgery, radiosurgery) and likely multiple biological therapies aimed at different biological properties of the tumor cells such as increased proliferation, vascularization etc. The treatment strategies will likely not be the same for all patients, but must be individualized and altered as the tumor and patient characteristics change with time. He pointed out that schwannomas are not driven by just one genetic alteration, but rather multiple pathways and thus, monotherapy will not be the holy grail.

“With Novartis we will evaluate Nilotinib in a single arm Phase2 study on growing vestibular schwannomas (VS) based on serial MRIs (>15% in 3mths). Rationale is based on our published pre-clinical work. 30 patients will be enrolled (per statistical advice), with both sporadic and NF2 associated VS eligible. Patients will receive 400mg Nilotinib bid PO. Tumor response will be monitored with serial MRI using volumetric analysis at 1,3mths and q3mths for 2yrs. Treatment duration will be 1yr.” - Dr. Guha

Abhijit Guha, FACS, FRCSC, MD, MSc, is co-director of the Arthur & Sonia Labbatt Brain Tumour Research Centre at the Hospital for Sick Children’s Research Institute and holds the Alan & Susan Hudson Chair in Neuro-oncology at the University of Toronto. Dr. Guha also undertakes clinical trials in surgical neuro-oncology as a neurosurgeon-scientist based at UHN’s Toronto Western.

The vision for the program is to attract new investigators to NF research, support innovative research and develop mutually beneficial relationships with research institutes, universities, and health organizations to ensure that NF is incorporated into research agendas across Canada and world-wide.  

We are pleased that the research program will be strengthened through our newly formed partnership with the Canadian Institute of Health Research under the Small Health Organixation Program (SHOPP).

CIHR Master’s Awards under the Small Health Organization Program (SHOPP):

These awards are available on a one-to-one matching basis.

Master’s Awards (2)

CIHR and NF Canada will provide $8,750 each for a total of $17,500 for 1 year.

Apply now!

The Shriners Hospital for Children, located in Montreal, has been operating since 1925 and is one of 22 Shriners hospitals across North America. It is an orthopaedic hospital offering special care to children from around the world under the age of 18. The Shriners Hospital is equipped and staffed with skilled specialists to provide comprehensive treatment for children with congenital bone diseases such as osteogenesis imperfecta (OI) and a wide range of orthopaedic problems including; scoliosis, cerebral palsy, limb length discrepancy, fractures and dislocations. In addition, the Shriners Hospital is also involved in basic and clinical orthopaedic research.

Regular orthopaedic clinics offered by the hospital include scoliosis, spinal deformities, OI, metabolic, hip, neuromuscular disorders (cerebral palsy, spina bifida), rheumatology, plastics and prosthetics. The Shriners Hospital works in conjunction with the Montreal Children’s Hospital in order to continue providing the best care for its patients.

Neurofibromatosis: Orthopaedic Manifestations

Neurofibromatosis type I (NF1) is an autosomal dominant disorder. It is one of the most frequent genetic disorder in man. The disease can also occur sporadically and may affect the skin, nervous tissues, bones and soft tissues. Often, its full manifestations are not present until after puberty. However, in approximately 50% of cases, significant musculoskeletal disorders may occur during early childhood.

Orthopedic Manifestations of Neurofibromatosis:

The orthopaedic manifestations of NF1 can be categorized into basically 4 components including:

• Spinal deformities
• Pseudoarthrosis
• Overgrowth
• Bone erosion
• Rare complications

Spinal Deformities:

Approximately 60 % of neurofibromatosis patients have some form of spinal disorder including one of the following:

a) Scoliosis

Scoliosis is a lateral deviation of the vertebral column and rib cage resulting in an “S” shaped spine and rotated vertebrae.  This may cause uneven shoulders, hip deformities, and back pain. As a result of the rotated spine, a hump in the back is possible and long term cardiac and respiratory problems are a threat.

Scoliosis due to neurofibromatosis generally results in a short and sharply angulated curve either on the left or right side. The scoliosis is usually progressive and can be accompanied by other spinal deformities. It is often a result of intraspinal lesions such as tumors.

There are basically two patterns of scoliosis which are observed in neurofibromatosis. These include:

• Dystrophic scoliosis which usually involves 1-6 vertebrae and is characterized by short segmented, sharp angled curves accompanied by strong rotation of the vertebrae. Pedicle erosion, foraminal enlargement, spinal canal widening, development of vertebral soft tissue mass, and twisting of the ribs, referred to as penciling, can also occur.  These features are most likely due to primary bone dysplasia as well as intraspinal lesions or neurofibromas (dumbbell tumors). Dystrophic scoliosis may lead to a vertebral body dislocation, destabilization of the spine and eventual severe deformity. For curvatures exceeding 20-40o, surgical treatment is usually recommended during childhood. Treatments include bone grafts or a posterior\anterior fusion with or without internal fixation. Brace treatment is generally not sufficient for treating dystrophic curves.

• Nondystrophic scoliosis is the type of spinal deformity most commonly affecting NF1 patients. It resembles idiopathic scoliosis (common abnormal spinal curvatures with unknown cause) and usually affects 8-12 vertebrae.  Depending on the severity of the deformation, it can be treated using a brace for curves less than 35o.  These curves, however, may progress into dystrophic scoliosis.

b) Kyphoscoliosis

Kyphoscoliosis is a posterior deviation of the vertebral column (commonly referred to as “hunchback”) resulting in perturbation of the thoracic region of the spine and back.  Approximately, 10 % of patients with NF1 have kyphoscoliosis. The development of paraplegia (paralysis of the lower part of the body) can be observed as a result of excessive tension on the spinal cord. Surgical treatment of kyphoscoliosis is often complicated by the presence of spinal neurofibromas and dural ectasia (swelling of the ‘dura’ which is the outer membrane of the spinal cord). Anterior and posterior spinal fusions are often necessary.

c) Other spinal deformities

Spinal deformities observed less frequently in patients with NF1 include cervical spine disorders, lordoscoliosis (An abnormal forward curvature of the lumbar region which is the lower area of the spine) and spondylolisthesis (slippage of one vertebra onto another resulting in stiffness in the back).

2) Pseudoarthrosis:

Pseudoarthrosis is a form of abnormal union or non union between two bone segments resulting in a false joint formation. This can occur following a fracture or bending but can also be present at birth. Most commonly, this involves the tibia but the ulna, femur, clavicle, radius and humerus may also be affected. 

Congenital pseudoarthrosis of the tibia causes abnormal bone development, bone weakening, and anterolateral bowing. It can occur in 1-2 % of patients with NF1. Limb length discrepancy due to growth deficiencies is often associated with this condition. Symptoms can become apparent within the age of 1 and fractures resulting from tibial bowing can manifest within 2-2.5 years.  There are two types of pseudoarthrosis of the tibia:

• Type I (nondysplastic): characterized by anterolateral bowing with increased bone density and thickening of the bone. This type rarely causes fractures.

• Type II (dysplastic): Characterized by anterolateral bowing and usually leads to fracture as well as pseudoarthrosis of both tibia and fibula. The development of cystic lesions adding on to bone fragility is often observed.

Treatments for pseudoarthrosis usually consist of using braces to prevent fractures. Surgical interventions include rod insertion (telescoping or not) which may be combined with bone graft.  Several surgeries are often necessary to get a solid bone.  The use of external fixators (Ilizarov) helps improving clinical results. Bone graft (vascularized fibula) also remains an option.  Amputation may be recommended after several failures.

3) Bone Overgrowth:

Patients with NF1 often have zones of bone and soft tissue overgrowth in the lower extremities, head or neck.  This results in the abnormal enlargement of a particular limb or body part often causing the skin to become rough and have an elephant-like appearance. Limb length inequality which results from the asymmetrical overgrowth can be treated with epiphysiodesis (growth arrest) of the long leg around the age of puberty.

4) Erosive defects of bone

Bone lesions appearing as pits may occur either due to cystic lesions from neurofibromatosis or from a contiguous tumor.

5) Rare Complications:

Some rare complication from NF1 inlcude hip dislocations, subperiosteal bleeding and malignant tumors (neurfibrosarcomas)

Conclusion:

Symptoms of NF1 vary highly in severity and can develop starting from birth through adulthood. The diagnosis and treatment of the common orthopaedic manifestation including scoliosis, pseudoarthrosis, neurofibromas and overgrowth is a challenging process. All current existing treatments are aimed at restoring function and improving the quality of life of the patient.

F Fassier, MD. FRCSC

Department of Surgery, Division of Orthopedic Surgery, McGill University, Montreal, Quebec
Chief of Staff, Shriners Hospital for Children
1529, Cedar Avenue, Montreal, Quebec, Canada H3G 1A6
Tel: (514) 842-4464
E-mail: ffassier@shrinenet.org

Rehabilitation centres for persons with physical deficiencies can offer services to these children if they need a specialized or highly specialized service. This type of service may help bring about significant gains in the performance of one or more daily living activities. The prognosis is then improved and may have a positive impact on development.

At the Centre de réadaptation en déficience physique Chaudière-Appalaches rehabilitation centre, children with NF1 are admitted to the childhood motor skills deficiency program. This program is intended for children aged from 0 to 17 years presenting a motor skill deficiency, delayed psychomotor development or dysphagia. Specific services include individual and group activities to support the integration of the child into day care, school and other living environments. There is also a mobility technical aids (wheelchairs, orthoses, etc.) department, as well as pediatric and orthopedic clinics.

In terms of cognitive disorders, neurofibromatosis type 1 can affect children on different levels. In fact, these children are up to seven times more at risk of presenting learning disorders than the general population. Such disorders are present among 30% to 70% of people with NF1 (compared to about 10% for the general population). Each case is unique, but several common traits may be present. The most frequently reported disorders are as follows:

• Intellectual quotient slightly below normal
• Symptoms of a non-verbal dysfunction syndrome:
  • Visuo-spatial deficits (emphasis on external stimuli and details, difficulty in seeing the whole picture, weakness in forming letters and writing legibly, difficulty in getting organized in time, in space and with school materials, or difficulty when younger in telling time from a traditional watch)
  • Tactile deficits
  • Gross motor skill disorders (hypotonia, motor incoordination)
  • Difficulties in mathematics and non-verbal problem solving
  • Difficulties with new situations
  • Great verbosity
  • Poor visual decoding
  • Weak social skills
  • Categorization difficulties

• Receptive (dyslexia) or expressive (dysorthographia) written language disorders
• Attention deficit disorder with or without hyperactivity
• Impairment of so-called executive frontal functions: social skills, cognitive flexibility or self-control.

The neuropsychological evaluation then becomes important, as there is no constant profile in NF1. The results of this evaluation reveal how the child can best process information to maximize understanding and subsequent recollection. The problems that can have an impact on learning must be identified in order to offer appropriate teaching aids. A series of recommendations is then proposed to the parents and school professionals, based on the child’s profile. The evaluation can be done at any age, every time the presence of difficulties affecting the following functions is suspected:

• Attention and memory functions
• Perception, visuo-spatial organization or non-verbal reasoning functions
• Motor and praxis functions (disturbance of propositional or voluntary movements)
• Executive functions, which concern the use of appropriate strategies to resolve tasks in order to achieve a goal; this ability includes strategies for planning, impulse control, active memory search processes, flexibility in thoughts and actions, as well as programming or regulation of social conducts and behaviours
• Language functions in spoken and written language comprehension or expression.

The role of the psychologist consists in doing part of this evaluation and in accompanying the child and his or her family following receipt of the diagnosis. The psychologist can provide psychotherapeutic support in relation to the after-effects of the disease (for example, esthetic impacts, concerns and anguish about the future or grieving related to the after-effects). Anxiety can be present in up to 33% of cases.

There are consequently psychology and neuropsychology services. There is also the possibility of referral, according to needs, to appropriate occupational therapy and physiotherapy resources, in the presence of hypotonia or motor incoordination. There can also be remedial instruction or speech therapy support at school, in the case of learning disorders. Medication can be considered if there is a significant attention deficit disorder. Parents can also benefit from the personal support of a social worker to help them better adjust to the situation in order to prevent overprotection, lack of autonomy, poor social integration and low self-esteem in their child.

In sum, services are offered according to needs. Each child is unique, and all children must be given the best springboard to optimize their development!

Isabelle Ouellet
Psychologist and neuropsychologist
Centre de réadaptation en déficience physique Chaudière-Appalaches

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Neurofibromatosis (NF) is an umbrella name for three separate genetic disorders that share a common manifestation - tumour growth in the tissues that surround nerves. NF can result from a spontaneous genetic alteration or is inherited from one or both parents. While most of the tumours are benign, they can occasionally become malignant. Symptom manifestations and their severity vary greatly in all three forms of NF, making each form a distinct and complex genetic disorder. NF is equally prevalent across the world and is not limited by any gender, racial, social or economic boundaries.

The three Neurofibromatoses are chronic, progressive disorders that pose different challenges at different stages of life. Living with a lifelong disorder requires a person to manage not only the physical symptoms, but to find ways to cope with new circumstances that may impact psychological, social, economic, and quality-of-life issues. These psychosocial issues affect not only the individual with Neurofibromatosis, but also family members and other loved ones.

The Three Types of Neurofibromatosis

• Neurofibromatosis Type 1 (NF1)
  The most common genetic disorder affecting approximately 1 in 3,000 to 4,000 births
• Neurofibromatosis Type 2 (NF2)
  A less common form, affecting approximately 1 in 40,000 births
• Schwannomatosis
  Appears to occur as often as NF2, affecting approximately 1 in 40,000 births

NF Type 1

Neurofibromatosis Type 1 (NF1) is the most common single gene disorder to affect the human nervous system and affects approximately one in 3,000 to 4,000 births. NF1 causes developmental changes in the nervous system, skin, bones, and other tissues. Half of the cases of NF1 result from a spontaneous genetic mutation, meaning there is no known cause, while the remainder of cases are inherited from one or both of the parents. NF1 occurs with equal frequency in males and females and has been identified in all ethnic, social and economic groups around the world.

NF1 affects each person differently. Some people are quite mildly affected and may not experience any impacting symptoms of the disorder while others are more severely affected and require increased medical treatment. Each individual with NF1 - even those in the same family - can be affected in a completely different manner. Overall, it is estimated that about half of the people with NF1 are moderately to severely affected. While it is very unlikely that any one person diagnosed with NF1 will experience all of the associated complications, it is difficult to predict the severity or progression of the disorder in any individual case.

Download Fact Sheet for more information on NF1

NF Type 2

Neurofibromatosis Type 2 (NF2), also called Bilateral Acoustic Neurofibromatosis, is very different from NF1 and is a much more rare genetic disorder, affecting about one in 40,000 births. Alterations in the NF2 gene cause Neurofibromatosis Type 2. The onset of NF2 is unique to each individual. Some may develop their first symptoms during their late teenage years or in their early 20’s. A few individuals develop symptoms in childhood, while others live without any signs of the disorder until their 40’s.

NF2 is characterized by benign (non-cancerous) tumours that grow on the cranial and spinal nerves. There are few visible signs of NF2; however, there are symptoms that can indicate the presence of the disorder. NF2 often causes slow-growing, benign tumours to grow along the eighth cranial nerve, which leads from the brain to the inner ear. These tumours are called acoustic neuromas or vestibular schwannomas. The most common early symptoms are hearing loss, ringing in the ears (tinnitus) and loss of balance caused by tumours growing on the nerve from the ear to the brain. If tumours are growing in other parts of the brain, signs and symptoms vary according to location and can include seizures, changes in vision or sensation and fluid build up in the brain.

Download Fact Sheet for more information on NF2

Schwannomatosis

Schwannomatosis is a rare form of NF that has only recently been recognized. This disorder appears to occur as often as NF2 approximately one in 40,000 births. Individuals with Schwannomatosis develop multiple schwannomas on cranial, spinal and peripheral nerves, but they do not develop vestibular tumours and do not lose their sense of hearing. Schwannomas are tumours that come from the cells that form a protective sheath around the body’s nerve fibers. They are usually benign and when possible, are surgically removed. They usually appear as a single tumour and rarely will they develop into multiple tumours. Affected individuals usually have much greater problems with pain than with neurological disability, although as with all forms of NF, schwannomatosis may vary greatly between patients. Many individuals with schwannomatosis go several years before the source of their pain is realized because they have few or no neurological symptoms.

Download Fact Sheet for more information on Schwannomatosis

The Future for NF Patients

There is no cure for NF and to this day, the Canadian medical community is largely uninformed and has difficulty making an inaccurate and timely diagnosis. Treatment strategies for NF are still in the trial stages. Our goal is to bring awareness and education to the medical community so that together, we can face the future of Neurofibromatosis.

It is difficult to predict the severity or progression of NF in any individual case. It is important to recognize that despite varying challenges, most people with NF can live long and rewarding lives.