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In the Neurofibromatosis Research Roundup we highlight a sample of neurofibromatosis-focused publications which have appeared in the recent medical and scientific literature.  All references mentioned are listed at the end of this document. For more information on any individual publication, visit PubMed at www.pubmed.gov. Here, you will be able to access the abstract for any article mentioned - and in some cases the full article - at no charge. 

NF2 Biology and Drug Targets The principle behind the recently reported promising trial of bevacizumab (Avastin) in NF2, where the drug was seen to reduce tumor volume and restore hearing in a small number of patients, is that the drug targets vascular endothelial growth factor and in essence normalizes blood vessel growth which is disrupted in the tumors. Wong et al. review the rationale for VEGF-targeted drug therapies in NF2 in mouse models, examining the underlying biological changes of the tumors in response to this therapy. This study shows that anti-VEGF therapy normalizes the vasculature of schwannoma xenografts in nude mice and successfully controls the tumor growth, probably by reestablishing a natural balance between VEGF and semaphorin 3 signaling. In a Children’s Tumor Foundation funded research study, Ammoun et al. report a study that examines the rationale for testing drugs that target receptor tyrosine kinases (RTKs) as candidate NF2 therapies. Examining surgically removed human vestibular schwannoma (VS) tissue, phosphorylated (active) RTK signaling is abnormally high in VS tumors. The drug lapatinib which inhibits this signaling was then tested on human VS explants and found to quiet these pathways and reduce cell proliferation.  (The Children’s Tumor Foundation currently funds a pilot Phase Zero clinical trial Phase Zero of lapatinib in NF2). Bensenor et al.examine the question of how the NF2 protein merlin functions inside the cell to control growth. Using a fly derived cell model, they found that fly merlin protein forms particles in the cell that move up and down microtubules and in this way move around inside the cell.  Stamenkovic and Yuprovide a review merlin function.

NF1 Biology and Drug Targets

Children’s Tumor Foundation-funded research by Turbyville et al. demonstrates promise of Schweinfurthin A, a drug originally purified from a natural plant-derived product, as a treatment for NF1-related malignancies glioblastoma and astrocytoma.   The drug halts the growth of human tumor cells but not healthy cells derived from mice, apparently acting via blocking signaling target Rho. These findings suggest Schweinfurthin could have a tumor-specific mode of action- an exciting possibility for future development of drugs effective against NF1 malignancies.  

A number of recent papers examine the biology of optic pathway glioma (OPG)in NF1.  Brown et al.demonstrate thatneurons in the NF1 brain but not in the peripheral nervous system are physically affected by their reduced levels of the NF1 protein neurofibromin. These affected cells are more likely to undergo apoptosis - programmed cell death - when stressed. The cause is pinpointed to impaired interactions between neurofibromin and levels of the cell signal cAMP.  The drug rolipram shows promise in reversing these physical cellular abnormalities and may be offer neuroprotection for treatment of the NF1 brain tumor optic pathway glioma (OPG).

To understand what causes OPG, Sun et al. determine that low cAMP levels are sufficient for tumorigenesis in an NF1 mouse model of OPG; but that CXCL12 expression alone is not sufficient to trigger OPG.  Kim et al.examine the structural changes that occur in the optic nerve as tumors progress in an Nf1 mouse model, information that can help understand the evolution of these tumors and how to intervene with appropriate therapy. 

Investigating the cellular origin of malignancies that can arise from plexiform neurofibromas in NF1,Chai et al. examine MicroRNAs (miRNAs) in NF1. miRNAs are frequently deregulated in human tumors, and play important roles in tumor formation and show that a miRNA called miR-10b may play an important role in NF1 tumorigenesis through targeting neurofibromin and RAS signaling. In the same vein Riddle et al.examine whether levels of CD44 – a transmembrane glycoprotein - and p53 - a tumor suppressor gene - may serve as indicators of malignant progression of neurofibroma to MPNST.  44 tumors from 33 NF1 patients were examined. Results suggest that p53 mutation is a factor in malignant transformation and progression of neurofibroma and 70% of benign neurofibroma demonstrated some, usually focal, CD44 positivity. Pongpudpunth et al. examined cells within neurofibromas that express nestin – a cell marker usually associated with immature cells and therefore potentially those that might give rise to malignancy. Neurofibromas from patients with NF1 were examined and compared to neurofibromas from patients without NF1 but with spontaneous neurofibroma tumors. A significant population of nestin-positive progenitor cells was seen in in neurofibromas from NF1 patients but not in tumors from on-NF1 patients suggesting these cells may be worth exploring as a source of malignancy. Staser et al.review the underlying biology and genetics of NF1 and the key emerging role of mast cells in promoting tumor growth and as a target for therapeutic intervention.

Finally In a rather unusual paper, Robinson et al.demonstrate the existence of motor deficits in an NF1 mouse model and correlate these impairments with altered brain function.

NF2 Clinical Management

Neary et al. have developed a questionnaire for the purposes of measuring the primary and secondary quality of life impacts of NF2; the survey has been piloted in the UK.

Lim et al. report on a case of tanycytic ependymoma, a rare subtype of ependymoma rarely seen in NF2, in a 16 year old girl.  MRI revealed an intramedullary lesion within the upper cervical spinal cord, which was removed surgically. Pathology revealed a rare morphology that could be misinterpreted as pilocytic astrocytoma or other tumor type.  The authors encourage increased awareness of tanycytic ependymoma among neurosurgeons and pathologists to ensure appropriate management and treatment. 

Sisk et al.review the clinical feature of epiretinal membranes (lesions in the eye that cause reduced visual acuity) and from a study of 4 patients propose these as a novel predictor of NF2 severe phenotype in otherwise asymptomatic children. 

A controversial area in NF2 clinical management, radiosurgery was a focus of the NF2 meetings in Las Vegas, with a conclusion that there is a place for radiosurgery in NF2 under certain circumstances such as small and difficult to reach tumors (to be detailed in the forthcoming recommendations paper from that meeting).Sharma et al. present a review of the use of Gamma Knife radiosurgery on tumor control and hearing preservation in NF2. A tumor control rate of 87.5% is reported with 33.3% tumor regression.  Hearing preservation of in 66.7% was seen but the group acknowledges that long term follow up is key to fully evaluate the application and outcome of this technology.

Since its introduction, the use of the auditory brainstem implant (ABI) for hearing restoration in NF2 has grown in popularity and  has also been extended to adults and children without tumor conditions. Colletti et al. do a retrospective analysis of 114 individual ABI surgeries (83 adults and 31 children) performed between 1997 and 2008 and find that overall ABI has a low rate of complications, especially in NF2. In another paper, Schwartz et al. report the first case of trigeminal neuralgia resulting from an ABI cable’s nonvascular compression in an NF2 patient.

NF1 Clinical Management – Tumors

The complexity and variety of tumors that can develop in NF1 present a challenge to the clinician managing these cases and aiming to recognize the appearance of tumors as early as possible so hat appropriate intervention can be given.  A few recent clinical papers address this theme.Cavallaro et al. ponder the question of how such a complicated clinical condition as NF1 can be effectively managed by one clinical center at Sapienza University, Rome, Italy. They describe their Center’s experience of trying to accomplish this through Italy’s National Project for Diagnosis and Treatment of Rare Diseases. They emphasize the importance of annual clinical evaluation, specialize centers that include a multidisciplinary pool of clinicians and earliest possible detection of complications and especially potential malignant transformation of tumors. Finally,Sbidian et al. present the concept of a clinical ‘NF1 Score’ – a means of predicting whether an NF1 patient will develop internal neurofibromas and found this can be can be accurately predicted using a simple clinical score.  

A handful of papers review case studies of particular NF1 tumor types.  Pascual-Castroviejo et al.review cases of rare and largely benign brain tumors tumors seen in NF1 - tumors of the posterior fossa.   Segal et al.review a group of 44 cases of optic pathway glioma (OPG) in children with NF1 seen at their clinical center in Montreal.  Hernaiz Driever et al. review the natural history and management of low grade glioma in children with NF1.  Graf comments on the need for deeper research into the underlying cause and potential for management of glioblastoma a rare put potentially devastating brain tumor in NF1.

Stewart et al. review protocol for diagnosing and managing glomus tumors in NF1. These are benign painful tumors of the glomus body, a thermoregulatory shunt in the fingers and toes. Patients present with at least two symptoms of localised tenderness, severe paroxysmal pain, or sensitivity to cold. Women are affected more often than men. Surgery can be curative though tumor often recurs.

Boyd et al. examine pigmentation in café-au-lait macules seen in NF1 and find these vary in pigment intensity across people and within individuals that is unrelated to sun exposure.  The group is seeking a molecular rationale and clinical meaning to this.

In an unusual study,Friedrich et al. examine orbital dysplasia in NF1, and find that the underlying cause of this tends to be tumor-based rather than bone-based.  

NF1 Clinical Management - Bone Abnormalities

In one of the most intriguing recent reports in the area of bone abnormalities,Tikkanen et al. present two interesting clinical cases where congenital pseudarthrosis of the tibia has failed all interventional treatments and are due for amputation. Prior to this in an experimental approach, the patients receive mesenchymal stromal cell (MSC) transplantation of cells taken from the marrow of one of their healthy bones (iliac crest) and cultured in a dish for 3 weeks. The cells were then injected into the tibia bone marrow in a sponge scaffold and the patients followed for 10 months. In both cases bone formed at the pseudarthrosis site. Two of three treated bone defects healed though ultimately both patient shad to undergo amputation. Nevertheless this trial procedure suggests MSC transplantation may be a future therapy for NF1 pseudarthrosis. Heerva et al. examine osteoclast progenitors in the blood of 17 NF1 patients as they matured in cell culture, and found the resulting osteoclasts to have greater resorption capability and an abnormal morphology.

This past few months has also seen quite a few review articles offering different perspectives on NF1 bone abnormalities management. Wang and Liu review recent genetic and clinical developments of scoliosis in NF-1.  Koptan and Elmiligui review the clinical and radiographic outcomes of three-dimensional correction of severe rigid neurofibromatosis curves, a challenging bony manifestation of NF1. Feldman et al. provide a review of management approaches for NF1 orthopedic manifestations.

NF1 Clinical Management - Vascular Defects

Vascular involvement in the setting of neurofibromatosis type 1(NF1) has been well described and as reported in the Spring Research Roundup, progress is being made in understanding the molecular basis of this fairly rare but potentially devastating NF1 manifestation. The last couple of months have seen quite a few case reports on this interesting topic and these are summarized below.

Emori et al. present a case study of a female NF1 patient which is the first published report of a ruptured brachial aneurysm successfully reconstructed using a saphenous vein graft. Onkendi et al. describe a bilobed right internal carotid artery aneurysm extending to C2 in a 42-year-old lady with NF1 a. The aneurysm was excised with high exposure of the carotid artery and reconstruction performed using saphenous vein graft.   Higa et al.describe a case of coexisting vertebral artery aneurysms and arteriovenous fistulae in a 60 year old lady with NF1. The case was ultimately resolved with intubation and eventual repair through endovascular techniques. Emrecan et al. report a case of ruptured aneurysm in the highly unusual location of the profunda femoris artery in NF1, in which surgical intervention was successful. Santin et al.report a case of an acute spontaneous subclavian artery rupture in NF1 in which an endoprosthesis stent graft was placed.

NF1 Learning Disabilities

Researchers continue to unravel the fine features of NF1-related cognitive defects.Sangster et al. examine 26 pre-school children with NF1 compared with 21 unaffected children and demonstrate in NF1 a downward shift in IQ, poor visuospatial constructional skills, and inattention as well as deficits in working memory and suggest that at least some NF1 cognitive deficits can be identified - and intervention done - in the preschool-age group. Cutting et al. focus on reading disabilities in NF1 and found that while kids with NF1 reading disabilities function in some ways the same as kids without NF1 but with reading disabilities, the kids with NF1 are set apart by pronounced visuospatial deficits.  

Former CTF Young Investigator Awardee Carrie Shilyansky and colleagues presented two recent papers on the theme of learning disabilities. One report (Shilyansky, Lee and Silva) demonstrates further the biological role of the NF1 protein neurofibromin in normal brain function and how this is disturbed and leads to working memory deficits in NF1.  The other paper (Shilyansky et al.) is a terrific review paper on the molecular and cellular basis of NF1-related learning disabilities. Stornetta et al.review the Ras signaling pathway and its role in learning disabilities with a broad look across conditions ranging from NF1 and the established Ras-opathies such as Costello syndrome, to schizophrenia and Alzheimers disease.  Lo-Castro et al.reviewsthe occurrence ofAttention Deficit/Hyperactivity Disorder in a variety of genetic conditions including NF1.

NF2 Genetics

Seong et al. report mutational analysis in 7 Korean NF2 patients that reveals four novel NF2 mutations, including 2 splice-site mutations, 1 frameshift mutation and 1 missense mutation.

NF1 Genetics

Thomas et al. examine genetic clonality in NF1 dermal neurofibramas, as well as the potential involvement of other genetic loci. Somatic loss of heterozygosity was identified involving TP53 and RB1 in some tumors, a novel finding in benign cutaneous neurofibromas, possibly demonstrating an alternative molecular mechanism for tumor cause. Bottillo et al.report on the clinical and molecular features of a family where NF1 occurred in two of three siblings, as well as in one granddaughter, of unaffected parents. Linkage analysis revealed a disease-causing deletion encompassing three NF1 gene exons in affected individuals; the mutation occurred on the paternally derived allele, and was present in about 10-17% of the paternal sperms, raising the potential of a germline mosaicism in the probands' father. Germline mosaicism is believed to explain the recurrence of NF1 in offspring of unaffected parents.  Jeong et al. present a single NF1 patient with a mosaic Y chromosome loss in malignant peripheral nerve sheath tumor and suggest this may be involved in the transformation of benign plexiform neurofibroma to MPNST.

Two papers focus on NF1 genetic microdeletions. Pasmant et al. provide a review fromthe NF France Network characterize NF1 microdeletions in 70 unrelated NF1 microdeleted patients and confirm the existence of a contiguous gene syndrome with a significantly higher incidence of learning disabilities and facial dysmorphism in microdeleted patients compared to patients with intragenic NF1 mutations.  Bengesser et al. identify a novel type of recurrent NF1 microdeletion. 

                From a study of 29 patients, Mautner et al.present a case for deletion analysis as a predictive tool, since large deletions occur in 5% of NF1 patients and are associated with severe manifestations.  Early detection could allow for early intervention and therapy in this population.

                Muram-Zborovski et al. report two individuals - 4 year old and 11 year old boys - with NF1 exon 22 mutations, clinical diagnosis of NF1 but - as is often the case with exon 22 mutation cases - no major skeletal or tumor features.  In view of the emergence of SPRED-1, an NF1-like condition with a milder prognosis, it becomes particularly important to determine or eliminate a genetic diagnosis of NF1 in these mildly clinically affected individuals.

Schwannomatosis

Hadfield et al.  examine whether mutations in SMARCB1 – the candidate schwannomatosis gene – are also responsible for multiple meningiomas, and found in a study of 47 patients with multiple meningioma unrelated to NF2, that this is not the case.

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Graf N. (2010) Glioblastoma in children with NF1: the need for basic research. Pediatr Blood Cancer. 54(7):870-1.Comment on: Pediatr Blood Cancer. 54(7):890-6.

Hadfield KD, Smith MJ, Trump D, Newman WG, Evans DG. (2010) SMARCB1 mutations are not a common cause of multiple meningiomas. J Med Genet. May 14. [Epub ahead of print]

Heervä E, Alanne MH, Peltonen S, Kuorilehto T, Hentunen T, Väänänen K, Peltonen J. (2010) Osteoclasts in neurofibromatosis type 1 display enhanced resorption capacity, aberrant morphology, and resistance to serum deprivation. Bone.  Jun 9. [Epub ahead of print]

Hernáiz Driever P, von Hornstein S, Pietsch T, Kortmann R, Warmuth-Metz M, Emser A, Gnekow AK. (2010) Natural history and management of low-grade glioma in NF-1 children. J Neurooncol. Mar 30. [Epub ahead of print]

Higa G, Pacanowski JP Jr, Jeck DT, Goshima KR, León LR Jr. (2010) Vertebral artery aneurysms and cervical arteriovenous fistulae in patients with neurofibromatosis 1. Vascular. 2010 May-Jun;18(3):166-77.

Jeong SY, Park SJ, Lee SJ, Park HJ, Kim HJ. (2010) Loss of Y chromosome in the malignant peripheral nerve sheet tumor of a patient with Neurofibromatosis type 1. J Korean Med Sci. 25(5):804-8.

Kim KY, Ju WK, Hegedus B, Gutmann DH, Ellisman MH. (2010) Ultrastructural Characterization of the Optic Pathway in a Mouse Model of Neurofibromatosis-1 Optic Glioma. Neuroscience. Jun 23. [Epub ahead of print]

Koptan W, Elmiligui Y. (2010) Surgical correction of severe dystrophic neurofibromatosis scoliosis: an experience of 32 cases. Eur Spine J. May 27. [Epub ahead of print]

Lim BS, Park SQ, Chang UK, Kim MS. (2010) Spinal cord tanycytic ependymoma associated with neurofibromatosis type 2. J Clin Neurosci. 2010 17(7):922-4.

Lo-Castro A, D'Agati E, Curatolo P. (2010) ADHD and genetic syndromes. Brain Dev. Jun 21. [Epub ahead of print]

Mautner VF, Kluwe L, Friedrich RE, Roehl AC, Bammert S, Högel J, Spöri H, Cooper DN, Kehrer-Sawatzki H. (2010) Clinical characterisation of 29 neurofibromatosis type-1 patients with molecularly ascertained 1.4 Mb type-1 NF1 deletions. J Med Genet. Jun 12. [Epub ahead of print]

Muram-Zborovski TM, Vaughn CP, Viskochil DH, Hanson H, Mao R, Stevenson DA. (2010) NF1 exon 22 analysis of individuals with the clinical diagnosis of neurofibromatosis type 1. Am J Med Genet A. Jul 2. [Epub ahead of print]

Neary WJ, Hillier VF, Flute T, Stephens D, Ramsden RT, Evans DG. (2010) Use of a closed set questionnaire to measure primary and secondary effects of neurofibromatosis type 2.  J Laryngol Otol. 124(7):720-8. 

Onkendi E, Moghaddam MB, Oderich GS. (2010) Internal Carotid Artery Aneurysms in a Patient With Neurofibromatosis Type 1. Vasc Endovascular Surg. May 18. [Epub ahead of print]

Pascual-Castroviejo I, Pascual-Pascual SI, Viaño J, Carceller F, Gutierrez-Molina M, Morales C, Frutos-Martinez R (2010) Posterior fossa tumors in children with neurofibromatosis type 1 (NF1). Childs Nerv Syst. May 13. [Epub ahead of print]

Pasmant E, Sabbagh A, Spurlock G, Laurendeau I, Grillo E, Hamel MJ, Martin L, Barbarot S, Leheup B, Rodriguez D, Lacombe D, Dollfus H, Pasquier L, Isidor B, Ferkal S, Soulier J, Sanson M, Dieux-Coeslier A, Bièche I, Parfait B, Vidaud M, Wolkenstein P, Upadhyaya M, Vidaud D; members of the NF France Network. (2010) NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype. Hum Mutat. 31(6):E1506-18.

Pongpudpunth M, Bhawan J, Al-Natour SH, Mahalingam M. (2010) Nestin-Positive Stem Cells in Neurofibromas From Patients With Neurofibromatosis Type 1-Tumorigenic or Incidental? Am J Dermatopathol. May 24. [Epub ahead of print]

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Stewart DR, Sloan JL, Yao L, Mannes AJ, Moshyedi A, Richard Lee CC, Sciot R, De Smet L, Mautner VF, Legius E. (2010) Diagnosis, management, and complications of glomus tumours of the digits in neurofibromatosis type 1. J Med Genet. Jun 7. [Epub ahead of print]

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Sun T, Gianino SM, Jackson E, Piwnica-Worms D, Gutmann DH, Rubin JB. (2010) CXCL12 alone is insufficient for gliomagenesis in Nf1 mutant mice. J Neuroimmunol. May 27. [Epub ahead of print]

Thomas L, Kluwe L, Chuzhanova N, Mautner V, Upadhyaya M. (2010) Analysis of NF1 somatic mutations in cutaneous neurofibromas from patients with high tumor burden. Neurogenetics.  Apr 1. [Epub ahead of print]

Tikkanen J, Leskelä HV, Lehtonen ST, Vähäsarja V, Melkko J, Ahvenjärvi L, Pääkkö E, Väänänen K, Lehenkari P. (2010) Attempt to treat congenital pseudarthrosis of the tibia with mesenchymal stromal cell transplantation. Cytotherapy. May 31. [Epub ahead of print]

Turbyville TJ, Gürsel DB, Tuskan RG, Walrath JC, Lipschultz CA, Lockett SJ, Wiemer DF, Beutler JA, Reilly KM. (2010) Schweinfurthin A selectively inhibits proliferation and Rho signaling in glioma and neurofibromatosis type 1 tumor cells in a NF1-GRD-dependent manner. Mol Cancer Ther. 9(5):1234-43.

Wang Z, Liu Y. (2010) Research update and recent developments in the management of scoliosis in neurofibromatosis type 1. Orthopedics. 1;33(5):335-41.

Wong HK, Lahdenranta J, Kamoun WS, Chan AW, McClatchey AI, Plotkin SR, Jain RK, di Tomaso E. (2010). Anti-vascular endothelial growth factor therapies as a novel therapeutic approach to treating neurofibromatosis-related tumors. Cancer Res. 70(9):3483-93.