8/27/2015 Disclosures Neurofibromatosis 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 neurofibromas 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) 1 8/27/2015 NF1 Diagnostic Criteria (must exhibit 2) Pathophysiology • 6 or more café au lait • Optic pathway glioma • NF1 gene located on chromosome 17 at band macules (CALs) >5 mm • 2 or more Lisch nodules q11.2 in prepubertal patients (iris hamartomas) ▫ 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 neurofibroma • 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 • Genetic testing 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 Photo courtesy of Google Images 2 8/27/2015 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… Photos courtesy of Google Images Photos courtesy of Google Images 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) Photos courtesy of Google Images 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 Photos courtesy of Google Images 3 8/27/2015 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 Photos courtesy of Google Images Management of optic gliomas 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 macrocephaly typically develop during adolescence. Images courtesy of Google Images Image courtesy of Google Images 4 8/27/2015 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 Images courtesy of Google Images “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 Images courtesy of Google Images 5 8/27/2015 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