Neurofibromatosis, type 1. Fawn Leigh, M.D.

Transcription

1 Neurofibromatosis, type 1 Fawn Leigh, M.D.

2 Neurofibromatosis Types Neurofibromatosis type 1 1 in 3,000 Neurofibromatosis type 2 1 in 25,000 Schwannomatosis 1 in 40,000

3 Neurofibromatosis, type 1 Incidence 1:3,000 Autosomal Dominant CNS & PNS Benign & Malignant Tumors NF1 gene: Located on Chromosome 17 q 11 Spanning 350 kilobases & 60 exons Neurofibromin: Protein product of the NF1 gene Tumor suppressor Down-regulating Ras Absence of Neurofibromin in NF1 => Loss of Ras inhibition Tumorigenesis

4 Diagnostic Criteria for NF-1 (2 or more of the following criteria) 6 or more café-au-lait spots (> 5 mm prepuberty, >15 mm postpuberty) axillary or inguinal freckling 2 or more cutaneous neurofibromas plexiform neurofibroma optic glioma 2 or more iris Lisch nodules characteristic bony lesions severe kyphoscoliosis pseudarthrosis/long bone bowing hypoplasia of the greater wing of the sphenoid first degree relative with NF-1

5 Café au LaitSpots Axillary Freckling

6 Skin, neck fold freckling

7 Neurofibroma

8 Same Gene (NF1) Divergent Clinical Expression LOW NEUROFIBROMA BURDEN HIGH NEUROFIBROMA BURDEN

9 Iris Lisch Nodules

10 Tibial Dysplasia 5% of NF1 But, ~80% with tibial dysplasia will turn out to have NF1

11 Optic Pathway Gliomas Type : a type of piloctic astrocytoma Growth rate: slow growing Grade: Low grade or type I tumors Symptoms: - Visual field deficits - Vision loss in one or both eyes - Involuntary movement of globe - Proptosis

12 Optic Glioma Pre-Chiasmal Optic Glioma Post-Chiasmal

13 Bilateral and Chiasmal Optic Gliomas

14 OPTIC PATHWAY GLIOMAS Age of onset, distribution, and visual loss associated with optic gliomas Am J Ophthalmol 2001;131:

15 monitor optic pathway gliomas 1. Ophtho Exam: Visual fields, VA 2. Imaging: MRI

16 Optical coherence tomography in the evaluation of NF-1 subjects with optic pathway gliomas. J AAPOS Dec;14(6): Chang L, El-Dairi MA, Frempong TA, Burner EL, Bhatti MT, Young TL, Leigh F. Duke Eye Center, Durham, North Carolina, USA.

17 Treatment of Optic Pathway Glioma Carboplatin Vincristine Clinical Trial: Evirolimus, an mtor inhibitor Refractory Optic Pathway Glioma Phase II

18 Plexiform Neurofibroma aka Peripheral Nerve Sheath Tumor(s) Cellular and collagen overgrowth Congenital Predominantly involves the nerve, but, may also involve muscle, connective tissue, vessels and overlying skin Cells include fibroblasts, mast cells, Schwann cells, axons, perineural cells, and endothelial cells Incidence- ~ 20% of individuals with NF1 Increased risk of malignant transformation

19 Plexiform Neurofibroma

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21 Plexiform Neurofibroma

22 Plexiform Neurofibroma

23 Measurement of Plexiform Neurofibroma Growth in Children by MRI Younger children had the most rapid growth of the plexiform tumor relative to change in body weight DombiE. et al. Neurology 2007; 68(9):

24 Histology of a Plexiform Neurofibroma +EMA, S100

25 Cross-section & Histology of a Normal Peripheral Nerve epineurium perineurium endoneurium

26 Peripheral Nerve in Cross Section Axon Myelin Sheath Schwann cell

27 Monitoring Plexiform Neurofibroma Clinical Changes History of symptoms that could indicate growth Pain, change in sensation, change in size, change in strength or change in organ function Physical examinations to assess growth. Location Radiological Changes X-Ray or CT scan MRI PET

28 Plexiform Neurofibroma

29 Infiltrating Aggressive Plexiform Tumor of Sciatic Nerve and Pelvic Plexus

30 Infiltrating Plexiform Neurofibroma on MRI Mautner VF, et al. Neuroradiology 2006; 48(3):

31 Vertebral Erosion from a Plexiform Neurofibroma with Malignant Degeneration

32 PET Scan Imaging of Plexiform Neurofibroma May reveal plexiform neurofibroma that are malignant Ferner recommended a cutoff of 2.5 for the PET Standard uptake value (SUV). Ferner R.E. J Neurol Neurosurg Psychiatry 2000;68: tumors. mean SUV for five malignant tumors was 5.4 (SD 2.4), range , Mean SUV for 15 benign tumors, which was 1.54 (SD 0.7,) range (Mann-Whitney U test=1.5, p (two tailed)

33 PET SCAN of PLEXIFORM NEUROFIBROMA Coronal Whole body 18FDG-PET image shows a plexiform neurofibroma at the thigh (arrow).

34 ? Angelov, L. Neurosurgery 43(1), July 1998, pp 56-64

35 Spine tumors

36 Spinal cord compression

37 Pain

38 Plexiform Neurofibroma Treatment Medical Treatment of Pain Frequent but intermittent pain Cooling - ice packs Drugs- gabapentin (Neurontin), pregabalin (Lyrica) anti-inflammatory medications. Continuous pain or pain with neurological problems Evaluate for malignancy and treat appropriately

39 Plexiform Neurofibroma Surgical Treatment Indications Organ or neurological compromise Airway compromise Spinal cord compression Major organs- liver, bowel, etc Severe disfiguring lesions especially of the face and neck Possible malignancy or need for biopsy to exclude malignancy Small superficial PN

40 Treatment of Plexiform Neurofibroma Surgery is still the first choice for treatment Chemotherapy for plexiform neurofibroma has not been proven to be effective but new chemotherapeutic agents are under study

41 Clinical Trials Phase I Phase II Phase III Phase IV Small Group Larger Group Large Groups After Marketed Safety Dosage Range Side effects Effectiveness Confirm effectiveness Compare to standard treatment Monitor side effects Post-Marketing Monitor Risks Benefits First Time Safety Compare & Confirm Long-Term Use

42 Plexiform Neurofibroma Drug Treatment Trials Agent Trial design Eligibility for PN Inoperable, disabling or Thalidomide Phase I dysfigurative Tipifarnib Phase I Inoperable Tipifarnib/placebo Phase II, double-blind, placebo controlled, crossover Inoperable, progressive Pirfenidone Phase I Inoperable Pirfenidone Phase II Inoperable, progressive Peg-interferon alfa-2b Phase I Inoperable, progressive for symptomatic Sirolimus Phase II Inoperable, progressive Gleevac Pilot Inoperable, progressive Sorafenib Phase I Inoperable AZD2171 Phase! Inoperable, paraspinal, extensive Combination: Methotrexate & Vinblastine Phase II Inoperable, progressive

43 Other Tumors & Malignancies Malignant Peripheral Nerve Sheath Tumors Gastrointestinal Stromal Tumors Gleevac Pheochromocytoma Ganglioglioma Leukemia: JMML Increased risk of breast cancer in women

44 Other complications in NF1 NeuroVascular NeuroEndocrine NeuroCognitive

45 Neurovascular NF1 Moya moya Hypoplastic vessels Stroke Aneurysm Pseudoaneurysm (Dural Ectasias)

46 Left Middle Cerebellar Artery Stenosis and Stroke S.-C. Tang et al. / Journal of the Neurological Sciences 243 (2006) 53 55

47 Morbidity/Mortality 1055 NF1 Deaths <40 CAUSE DEATHS Soft tissue sarcoma 20.9% Brain tumour 10.6.% Cardiovascular disease** 29.2% Rasmussen et al: Am J Hum Genet 68:1110, 2001

48 Cardiovascular Disease Hypertension Essential hypertension Renal artery stenosis Congenital heart disease Myocardial Infarction LV dysfunction

49 Cardiac function in NF1 patients with hypertension Mean age 12yo LV hypertrophy Increased left atrial size Diastolic function impaired (whereas, normal NF1 patients without hypertension) Tedesco MA1, Di Salvo G, Natale F, Graziano L, Grassia C, Calabrò R, Lama G. Early cardiac morphologic and functional changes in neurofibromatosis type 1 hypertensives: an echocardiographic and tissue Doppler study. IntJ Cardiol May 25;101(2): Friedman JM, Arbiser J, Epstein JA, Gutmann DH, Huot SJ, Lin AE, McManus B, Korf BR. Cardiovascular disease in neurofibromatosis 1: report of the NF1 Cardiovascular Task Force. Genet Med May-Jun;4(3): Review.

50 Cardiac features may be assoc d with large NF1 deletions 16 NF1 with large deletion in NF1 gene compared with 16 with non-deletion. 6 of 16 NF1 deletion patients but none of 16 non-deletion NF1 patients have major cardiac abnormalities (p = 0.041). Hypertrophic cardiomyopathy Congenital heart defects Nguyen R1, Mir TS, Kluwe L, Jett K, Kentsch M, Mueller G, Kehrer-Sawatzki H, Friedman JM, Mautner VF. Cardiac characterization of 16 patients with large NF1 gene deletions. Clin Genet Oct;84(4): doi: /cge Epub 2012 Dec 28.

51 NeuroEndocrine Precocious Puberty, esp Chiasmal tumor Pheochromocytoma (Short stature) >weigh risks/benefits carefully?tumor growth when considering GH in kids

52 Short Stature Distribution of sex and age standardized stature. NF1 patient measurements are from the National NF Foundation Database. Unaffected norms are from the National Center for Health Statistics and the Fels Institute. Reprinted with permission Szudek J, Birch P, Friedman JM. J Med Genet. 2000;37: Copyright British Medical Journal. All rights reserved.

53 Learning in NF1 ADHD ADD Visual Perception Executive Function Language

54 Development Delay in NF1 Language Delay VPI Fine Motor Gross Motor

55 Neurofibromatosis & Neurofibromatosis type 1-like syndrome (NFLS) Neurofibromatosis Legius Neurofibromatosis type 1 Syndrome type 2 1 in 3,000 (SPRED-1) 1 in 25,000 Schwannomatosis 1 in 40,000

56 Legius Syndrom aka NF1-like Café au laits Learning disability Absent: Lisch nodule, neurofibromas, OPG, bone lesion, MPNST SPRED-1 gene a feedback regulator of RAS/MAPK signaling negative regulator of RAS pathway and interacts with neurofibromin, the product of the NF1 gene Chromosome 15 q 13.2 Brems H, Legius E: Legius syndrome, an Update. Molecular pathology of mutations in SPRED1. Keio J Med 2013, 62(4):

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58 Family Center for Neurofibromatosis At Massachusetts General Hospital