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Disclosures 1 and 2- What • I have no financial disclosures you need to know for primary care • Because I live in the world of pediatrics, I will briefly discuss off-label and investigational uses of drugs and devices

Beth Heuer, DNP, CPNP-PC, PMHS Division of Child Neurology/ Child Development Unit Children’s Hospital of Pittsburgh of UPMC

Learning Objectives Neurofibromatoses • Describe diagnostic criteria for NF-1 and NF-2 • NF1 and NF2 are autosomal dominant inherited • Identify common co-morbidities and multi-system disorders complications specific to each disease process ▫ Inheritance pattern for schwannomatosis less • Discuss disease management guidelines and clear. Seems to be autosomal dominant with treatment strategies incomplete penetrance • 3 distinct diseases, each associated with a different genetic mutation • Diagnosis based on clinical findings

Autosomal Dominant Inheritance Fast facts- NF1 • Affects ~1 in 3,000 people • Previously known as von Recklinghausen disease ▫ NOT ‘Elephant Man’ syndrome • Café au lait macules are seen in most individuals • Axillary/inguinal freckling is seen 90% of the time • Cutaneous are common • Many plexiform neurofibromas are internal and asymptomatic • 10% risk of developing a cancerous tumor • ~2/3 of patients will never experience significant health problems • Life expectancy is slightly reduced (most likely due to malignant tumors and vascular manifestations)

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NF1 Diagnostic Criteria (must exhibit 2) Pathophysiology

• 6 or more café au lait • Optic pathway • NF1 gene located on chromosome 17 at band macules (CALs) >5 mm • 2 or more Lisch nodules q11.2 in prepubertal patients (iris ) ▫ This gene encodes neurofibromin, which and 15 mm in longest • A distinctive osseous diameter in postpubertal suppresses tumors by downregulating Ras lesion patients proteins • A first-degree relative ▫ When the NF1 gene does not work, the Ras cell • 2 or more neurofibromas with NF-1 according to or 1 plexiform signaling pathway goes into overdrive these criteria • Genetic mutation leads to nonfunctional version • Inguinal or axillary of neurofibromin, resulting in tumors along freckling nerves throughout the body

NF1 Genetics Mosaicism

• Bloodwork may be negative for NF mutation, • 50% inherited; the other 50% are de novo or show positive mutation in only a percentage mutations of the lymphocyte sample • Other family members may have NF1 and not • Can skin biopsy 2 or more CAL macules know it (different sites) and look for gene mutation in • Extremely variable gene expression skin cells • is available to confirm a clinical • Can also consider testing urine sedimentation diagnosis (90-95% detection rate) or to make a (due to shedding of epithelial cells) to look for diagnosis when only one of the criteria is met mutation • False negatives or results of ‘unknown significance’ • Proportions of gonadal tissue may also contain the mutation

Segmental NF NF1 disease surveillance Early detection and treatment of complications • Occurs as a result of mosaicism • Clinical features limited to one area of the body • Yearly clinical evaluation • MRI of brain and Example: Skin lesions do not cross the midline ▫ Skin exam for new findings orbits (yearly from age 18 months until ~age ▫ Growth parameters 7) ▫ Neurologic exam • MRI of total spinal ▫ Skeletal changes canal ▫ Blood pressure ▫ Done if symptomatic ▫ Developmental assessment for back pain, ▫ Review of school progress numbness, weakness • Ophthalmologic exam ▫ May be done to determine presence of 2nd diagnostic criteria

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Skin findings Skin findings • Remember: “All that spots is Cutaneous neurofibromas Subcutaneous Neurofibromas not NF” and not all NF patients have café au lait spots…

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Plexiform neurofibroma Malignant peripheral nerve sheath tumors (MPNSTs)

• MPNSTs are the primary cause of early mortality in NF1 patients ▫ Mean age of presentation is 27.6 years ▫ 10% lifetime risk of developing a MPNST • Can develop from any benign plexiform tumor • Fast-growing cancers ▫ Often associated with severe pain ▫ Can be difficult to treat  Can adapt biologically and become resistant to treatment  5 year survival rate ~46 % (females>males)

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Ophthalmologic findings Management of skin lesions • Lisch nodules • Surgical resection • Optic nerve tortuosity ▫ Done when there is cosmetic disfigurement, pain, or alteration in function • Congenital ptosis • Neurofibromas do grow back • Sphenoid bone dysplasia • Radiation therapy is avoided ▫ May cause asymmetry ▫ Can stimulate the growth of plexiform and proptosis neurofibromas • Alternative techniques for dermal tumor removal ▫ CO2 laser ablation and electrosurgery ▫ Er:YAG laser treatment

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Optic glioma Optic Glioma

• ~20% risk of developing • Symptoms an optic pathway glioma ▫ Involuntary eye ▫ Most common type of movement central nervous system ▫ Proptosis tumor in NF1 ▫ Squinting • See in children as young ▫ Vision loss in one or as 18 months of age both eyes ▫ At risk until typically  Starts with the loss between ages 6-7 of peripheral vision • Typically benign, but can  May eventually lead ultimately impact vision to blindness ▫ Growth issues or precocious puberty

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Management of optic NF1 and CNS tumors • Monitored closely • Pilocytic astrocytomas ▫ Treated only when and if they interfere with vision ▫ Many tumors are low grade, asymptomatic and • May be unresponsive to chemotherapy require no treatment ▫ Urgent need for effective drug treatments! • Grade III and IV astrocytomas require  When tumors are present along optic pathway, aggressive treatment brainstem and cerebellum, surgery can cause ▫ Complete surgical resection + chemotherapy loss of vision or other function effective

Distinctive osseous lesions Scoliosis

• ~ 1/3 of patients with • Most common bone NF1 will develop some abnormality in NF1 type of bone abnormality • Seen in about 30% of ▫ Long-bone dysplasia patients. • A rapidly-progressing form ▫ Bone structural of kyphoscoliosis, called weaknesses dystrophic scoliosis, may ▫ Scoliosis develop between ages 3 and ▫ Osteopenia or 5 years of age ▫ Requires surgical osteoporosis correction. ▫ Short stature • Milder forms of scoliosis ▫ Relative typically develop during adolescence.

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MRI findings MRI Imaging • T2 hyperintensities (UBOs) found in up to 80% of children with NF1 ▫ Tend to disappear with age ▫ Predominantly show up in two regions of the brain: the globus pallidus (regulates voluntary movement), and the cerebellum(regulates balance) ▫ ?? correlation with Plexiform neurofibroma Spinal neurofibroma learning disabilities Image courtesy of Google Images Images courtesy of Google Images

Moyamoya Vascular abnormalities in NF1

• A variety of vascular abnormalities can occur in NF1, including aneurysms and stenosis ▫ Renal artery stenosis responsible for HTN  Routine blood pressure measurement is essential ▫ Most persons with NF1 are not routinely screened for vascular abnormalities ▫ Often progress silently without detection

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“Spinal NF1” Hormonal influences • Form of NF1 • Develop multiple spinal • Pubertal development typically normal tumors on both sides of ▫ Precocious puberty associated with optic chiasm the spinal cord & on the tumors nerve roots of the spine • During puberty, dermal neurofibromas have been reported to increase in number • Tumors may affect all ▫ May also see increase in axillary/inguinal freckling nerve roots. and CALs • Typically later onset • Plexiform and dermal neurofibromas tend to grow • May otherwise exhibit in pregnant NF1 patients only minimal features of ▫ Pregnancy may also trigger onset of hypertension and NF1 proteinuria

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NF1 and the GI tract Other co-morbidities • Oral tumors, such as • Below average height neurofibromas on the tongue • Above average head circumference ▫ Impact on speech and • High blood pressure (due to renal artery oromotor movement stenosis) • Gastrointestinal stromal • Headaches (20% of patients) tumors (GIST) affect up • Seizures (~7% of patients; ~3x > general to 1/3 of persons with population) NF1 • Small number of pheochromocytomas (adrenal ▫ 20% of NF1-related GISTs tumors) reported may become cancerous ▫ Must be carefully monitored • Peripheral neuropathy and appropriately managed

NF1 and learning disabilities NF1 and ADHD • Estimated that up to two- • Majority of patients show • Up to a half of children with NF1-related thirds of patients with average to low-average learning disabilities will also develop attention NF1 will develop some IQ scores form of learning • Neuropsychological deficit disorder (ADHD), with or without disability testing often indicated hyperactivity • Deficits in attention, ▫ Recommend retesting • Treatment principles the same as with general visual-spatial memory during big transition population with ADHD and executive function periods (school/work) ▫ Behavioral modification therapy

• Language problems ▫ Medication management • Academic ▫ Accommodations in school and home setting underachievement

Link to autism? Management of school issues

• 2013 UK study in Pediatrics • Determination of relative • Section 504 accommodation ▫ NF1 population prevalence estimate strengths and weaknesses plans • Educational testing and ▫ Learning and behavioral  24.9% ASD (95% C.I. 13.1%–42.1%) appropriate IEP services accommodations for ADHD  20.8% ‘broad’ ASD with partial features • School-based counseling for symptoms social concerns ▫ Accommodations for (95% C.I. 10.0%–38.1%) orthopedic concerns ▫ A total of 45.7% showing some ASD phenotype

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Social challenges Legius Syndrome • Concerns for body image • Isolation • Legius Syndrome, or NF1-like syndrome, occurs • Lower self-esteem due to mutations in the SPRED1 gene • Difficulty with social cues • Characterized by the presence of café-au-lait and speech pragmatics spots and learning disabilities • Concern for the future ▫ Does not lead to the development of tumors • Family planning • Approximately one to four percent of persons • Transition from pediatric who have café-au-lait spots will ultimately be to adult care diagnosed with Legius Syndrome rather than

NF1

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Neurofibromatosis-2 (NF2) NF2 Diagnostic Criteria OR Family history of NF2 (first Either • AKA: “bilateral acoustic neurofibromatosis” degree family relative) ▫ NF2 mostly affects the CNS, causing brain and • Presence of bilateral vestibular Plus spinal cord tumors schwannomas ▫ Either a unilateral vestibular schwannoma before age 30 • Birth prevalence is 1:25,000 OR • In the past, largely diagnosed in the teens or ▫ Any 2 of the following: twenties  Glioma  Meningioma ▫ There are an increasing number of diagnoses in  Schwannoma young children as well as older adults  Juvenile posterior subcapsular lenticular opacity (juvenile cortical cataract) Image courtesy of Google Images

NF-2 Pathophysiology NF-2 • Vestibular schwannomas • Studies show that more than • NF-2 gene on chromosome 22q 12.2 (acoustic neuroma) 90% of patients also suffer eye ▫ Lead to gradual hearing loss lesions. ▫ Codes a protein called • Meningiomas are seen in over ▫ Most common: juvenile ▫ Studies suggest that Merlin helps to organize cells half of persons with NF2 subcapsular cataracts in in the developing brain and contributes to ▫ Though largely benign, they young people can continue to grow and can ▫ Lead to vision loss effective myelination eventually become malignant • Other complications ▫ When Merlin is reduced or absent, these cells may • Ependymomas ▫ Tinnitus be disorganized • Risk of developing ▫ Headaches ▫ Leads to neuropathic pain and tumor formation schwannoma tumors along the ▫ Facial pain/numbness spine, in peripheral nerves, ▫ Balance issues and on skin ▫ General muscle wasting

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Vestibular schwannoma NF2 disease surveillance • Eye exam for presence of • Evaluation of hearing cataracts ▫ audiometry • MRI imaging ▫ electronystagmography ▫ brain ▫ ABRs ▫ spine

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Treatment options Schwannomatosis

• Removing a vestibular schwannoma when it is • Rarest, least-well-understood form of NF still small (in order to preserve cochlear nerve • Affects ~1:40,000 persons function), then placing a cochlear implant on the same side either during the same surgery or later ▫ Rarely seen in people before ages 20s-30s (to facilitate hearing) • May be associated with mutation of the SMARCB1 gene on Ch. 22 at locus proximal to • Auditory brainstem implant v. cochlear implant NF2 gene • Stereotactic radiosurgery • Multiple schwannomas on cranial, spinal and ▫ Radiation therapy remains controversial in its use in NF2 tumor management peripheral nerves ▫ The possibility of NF2 has to be excluded before a • Targeted biological therapies diagnosis of schwannomatosis is made

Emerging therapies Where to find help?

• Molecular-targeted drugs that stabilize signaling molecules involved in cell division and growth • Epidermal growth factor receptor (EGFR) inhibitors ▫ Erlotinib (Tarceva) • Vascular endothelial growth factor (VEGF) inhibitors ▫ Ranibizumab ▫ Bevacizumab (Avastin) Clinics that are part of the NF Clinics Network (part of the Children’s Tumor Foundation)

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References References • BC Neurofibromatosis Association (n.d.) A Parent’s Guide to • Tonsgard, J. (2006). Clinical manifestations and the Learn Disabilities Associated with Neurofibromatosis management of Neurofibromatosis Type 1. Seminars in Type 1. Victoria, BC: BC Neurofibromatosis Association Pediatric Neurology, 13, 2-7. • Garg et al. (2013). Neurofibromatosis Type 1 and Autism Spectrum Disorder. Pediatrics, 132 (6), e1642-e1648. • www.news-medical.net/news/20141215/UT- • Hersh, J. et al. (2008). Health supervision for children with Southwestern-researchers-identify-possible-therapy-to- Neurofibromatosis. Pediatrics, 121 (3), 633-642. treat-neurofibromatosis-type-1.aspx • Karajannis, M., Ferner, R. (2015). Neurofibromatosis-related • www.ctf.org tumors: emerging biology and therapies. Current Opinion in • www.nfnetwork.org Pediatrics, 27 (1), 26-33. • www.uptodate.com • Plotkin, S. et al. (2014). Update from the 2013 International Neurofibromatosis Conference. American Journal of Medical Genetics, Part A. DOI 10.1002.ajmg.a36754

Special thanks to.. Questions?

• Drs. Amy Goldstein and Kathy Gardner, for their • Contact information: [email protected] invaluable assistance in development of this presentation • Sinnika Davis, MSW

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