1. HPI A 7 year old girl is brought by his mother because she is concerned that she is “not keeping up with the other children.” The pt is in first grade and is struggling to keep up with peers in reading. Both mom and the teacher have noticed she has difficulty sitting still and often blurts out responses in class. Mom also notes she has “more birthmarks that she used too.” Per mom she has always had a lot of freckles under her arms, but now she has more dark skin patches. The patient also complains of intermittent L leg and L arm numbness (described as “tingles”) and weakness. List items in the hx that would you help you solve the case: 1.PMH/SH: 2.Birth Hx: 3.Social Hx: 4.Family Hx:

2. Further History Past Med/Surg Hx: Dx with scoliosis at school this year. No infantile spasms. Fell and broke humorus 8 mo ago. – Meds: none – Allergies: none – Immunizations: Up to date Gynhx: No signs of early puberty or vaginal bleeding Birth Hx: Normal vaginal delivery at term Family Hx: Dad has HTN and lots of “skin tags” and has to see lots of doctors. Social Hx: Lives at home with mom and dad. No sick contacts. Please list at least 3 items on your differential diagnosis 1. 2. 3.

3. DDx Neurofibromatosis – Type I – Type II Tuberous Sclerosis ADHD Learning Disability Tenia Versicolor McCune-Albright Syndrome Radiculopathy/Vertebral stenosis Beside each diagnosis list items you will look for on physical exam that would support or refute each one.

4. Physical Exam Vitals: T: 98.6° F, P: 75 bpm, BP: 120/75, RR: 12, SpO 2 : 99% on RA Gen: Energetic throughout exam. Skin: 7 brownish, smooth border, macules, the smallest measuring 7mm. There is obvious freckling in both axilla as well as the inguinal region bilaterally. There is one small area of lighter skin that is new per mom. HEENT: Head is without deformity. There are no rashes of the face. There are multiple hyperpigmented nodules on the patients iris (see pic) CV: wnl Resp: wnl Abd: wnl M/S: mild scoliosis. No other boney abnl. Neuro: AxOx3. CN’s II-XII intact. 4/5 strength in L leg and arm, 2+ reflexes throughout. Slightly decreased sensation in the L arm. Cerebellar function intact. What tests/evaluations (not imaging) would you order. (you may add more or use less than the numbers listed) 1. 2. 3. 4. 5. 6. Pt’s Father Pt’s Eye Exam

5. Tests CBC, CMP: wnl Wood’s Lamp Exam of Hypopigmented spot: – Negative fluorescence. Genetic Testing: + for NF1 (neurofibromin) mutation Testing of Visual Acuity: normal Hearing Screen: Normal Vanderbilt Assessment Tool for ADHD: positive GH: normal Order any imaging 1. 2. 3. 4.

6. Imaging 1.CXR: Quick test to see any major issues with thoracic bones 2.MRI thoracic spine for extremity symptoms 3.US Kidneys and Heart to check for angiomyolipomas and rhabdomyoma respecitively. *Done if you can’t rule out Tuberous Sclerosis Classic dumbbell shaped paraspinal neurofibroma with displacement of spinal cord likely causing the patients extremity symptoms.

7. Extra Imaging Bilateral Optic Gliomas Black arrows at top depicting neurofibromas on CXR Consider your DDx and write your diagnosis _____________________

8. Diagnosis: NF Type I Consider you DDx: DDxPositiveNegative ADHDHyperactivity at school, impulsivity. +Comments from teachers, + Vanderbilt screen, common with NF Alone, it doesn’t explain the physical findings Tuberous SclerosisAsh leaf lesion, mental delay,No adenoma sebaceum (reddish brown papules on nose, cheeks. Negative woods lamp on ash leaf. No infantile seizures Learning DisabilityFalling behind peers. SeemsPhysical findings of extremities, cutaneous findings. May be comorbidity but doesn’t explain all the findings Tenia VersicolorHypopigmented spotNegative woods lamp. Doesn’t explain extremity symptoms of developmental delay. Usually multiple locations and don’t tan in the sun. McCune AlbrightMultiple hyperpigmented macules, hx bone fracture Gigantism, facial bone abnormalities, café-au-lait spots are usually more irregular and located on back, normal Growth hormone Vertebral StenosisNumbness and tingling in extremitiesMultiple extremities involved, age

9. Therapy/Surveillance Check-ups – Evaluation for new neurofibromas and progression of lesions – Annual BP measurement and formal ophthalmologic evaluation – Neurodevelopmental assessment – Evaluation for skeletal changes (ie, scoliosis, vertebral angulation, and limb abnormalities) – Genetic Counseling Associated Tumors – Wilms – Pheochromocytoma – Juvenile CML Red Flags – Pain of unknown etiology – Weakness, numbness, tingling in the extremities – Change in balance or coordination – Change in vision – Change in intensity or frequency of headaches – Neurofibromas that change rapidly in size and/or color, or cause pain – Abnormal neurologic examination – Sudden onset of hypertension – Regression of cognitive skills or loss of developmental milestones – Significant deviation from established pattern of growth

10. Summary Multiple types of mutations (e.g. point, translocation, deletion, etc) in the NF1 gene which turns off a tumor growth factor – 50% of cases are inherited (AD) and 50% are de novo mutations. ADHD is not uncommon with NF, so screening in suspected children is warranted. Order of appearance: Café au lait spots, axillary freckling, Lisch nodules, and neurofibromas Lab tests and Imaging are driven by the clinical picture. – Ex. Urine metanephrines for pheochromocytoma if persistent HTN exists – Ex. MRI Orbits if you suspect optic gliomas or visual changes are present

11. Overview of NF Type I NIH Criteria – 6 or more café au lait macules >5mm (prepubertal), >15 mm postpubertal. – 2 or more NF’s or 1 plexiform type – Freckling – Optic glioma – 2 or more lisch nodules – Bony lesion – 1 st degree relative with NFI

12. NFI vs NFII References: http://www.jaapa.com/neurofibromatosis-type-1-von-recklinghausen-disease/article/197450/ http://www.uptodate.com/contents/neurofibromatosis-type-1-von-recklinghausens- disease?source=search_result&search=neurofibromatosis+children&selectedTitle=1~131#H6 NFINFII Chromosome/Protein17 (neurofibromin)22 (merlin) Lisch Nodules+- Café au lait spots++ Freckling++++ Cognitive Delay+- Cutaneous lesions++ Bilateral Acoustic Neuromas-+ Malignant Transformation+- Pigmented Plexiform NF’s+- Dumbbell tumors (spinal)Neurofibromasschwannomas