1. Skin Manifestations of Neurofibromatosis Type 1 (NF1)
Kevin P. Boyd, MD
Resident,
UAB Department of Dermatology
Good evening. I’d like to start by thanking Sheila for inviting me to San Diego Derm – I have had a great time – and I’d like to especially thank her for letting me speak on NF, which I try to do any chance I can get. The first half of this talk I am going to review NF with a focus on the recent literature and then the last half I am going to discuss some of the research that we have been doing.

2. A Little Light Reading…
Boyd KP, Korf BR, Theos A. Neurofibromatosis Type 1. J Am Acad Dermatol 2009; 61(1): 1-14.

3. NF1 vs. NF2
NF1
NF2
Many CALMs, skin fold freckles, many skin neurofibromas
Few CALMs, no freckles or skin neurofibromas

4. Diagnosis of NF1 DIAGNOSTIC CRITERIA Café-au-lait macules (≥ 6)
Skin fold freckling
Lisch nodules (> 2)
Optic pathway glioma
Skin neurofibromas (≥ 2) or plexiform neurofibroma
Distinctive bone abnormality
NF1 in a parent, child, or sibling

5. NIH Criteria for Diagnosis of NF1 in Children
This graph is from a study published in Pediatrics in 2000 and shows how the diagnostic criteria become more sensitive with the age of the patient. This was a group of children with NF1 and a negative FHx. At two years of age, 50% met diagnostic criteria, it jumps up to about 75% by age 4, which in most is probably due to the presence of freckling by 8 years of age, it is 90%, and is 100% by age 20. The take home point is that the criteria are extremely sensitive in adults, but not as sensitive in young children. I think this right here is the age where genetic testing impacts diagnosis.
Copyright © 2000 American Academy of Pediatrics
DeBella, K. et al. Pediatrics 2000;105:

6. Café-au-lait Macules (CALMs)
Common in the general population
Need at least 6 to diagnose NF1
Early sign of NF1
Appear by age 1
Darken with sun exposure
Often fade in adults
Not harmful or dangerous

7. Café-au-lait Macules (CALMs)
Treatment
Generally not necessary
Sun protection
Cosmetic cover-up
Lasers can lighten CALMs
Multiple treatments needed
Recurrence possible

8. CALM Research Projects
Are there significant spot-to-spot color differences among CALMs in a person with NF1?
CALM 2
Are these differences related to the inherited genetic change (mutation) in the NF1 gene?
CALM 3
Are these differences related to the combination of the inherited and acquired change in the NF1 gene?

9. CALM 1 Project Conclusions Reliable tool
Significant spot-to-spot variation independent of sun exposure
CALMs darken with sun exposure

10. CALM 1 - Variability
Whisker plot displays the variability of calms pigment within and among individuals

11. CALM 1 – Sun Exposure

12. CALM 1 – Distribution
4x more common on the trunk compared to the face and 2x more common on the trunk than the arms and legs; appear to be most concentrated on the lower part of the stomach and back

13. CALM 1(b) – Homogeneity

14. CALM 2 Project Requirements Analyze CALMs using a light meter
Patients with NF1
≥ 13 years old
Positive NF1 genetic test
Analyze CALMs using a light meter
Correlate mutation type with our results from the light meter
Positive results = proceed to CALM 3

15. CALM 2 – Results

16. Skin Fold Freckling Specific for NF1 First appear around age 3 to 5
Involve armpits, groin, neck, below breasts
Possible related to heat or friction
Not harmful
No treatment

17. Skin Neurofibromas

18. Skin Neurofibromas Bumps on or below the surface of the skin
Appear around puberty
Increase in size and number
Number highly variable
Pregnancy can cause growth
Low risk of cancer
Affect quality of life

19. Skin Neurofibromas No medical treatment – yet Treatment options
Simple excision
CO2 laser ablation
Electrocautery
Scar likely
Recurrence possible

20. Neurofibroma Research Project
Goal: Validate a tool that can reliably and objectively follow the growth of skin neurofibromas
Clinical trials
Define natural growth history
Correlate rate of growth with combination of inherited and acquired changes in the NF1 gene

21. Laser Scanner “La guillotine”

22. Neurofibroma Research Study

23. Other Skin Findings Juvenile xanthogranulomas Hypopigmented patches
Generalized hyperpigmentation
Glomus tumors
JXG reported at an increased frequency in children with NF1; triple association “NF1, JXG, JMML”; routine screening with cbc not recommended; sx incl hsm, lad, pallor; Multiple glomus tumors have been reported in several pts with NF1; presenting sx is severe pain in fingersdigits which may be misinterpreted as neuropathic pain poss from a spinal nf – but if you ask them they say the pain is trigerred by cold. Impo to recognize this b/c surgical exc relieves pain
Cambiaghi et al. Pediatr Dermatol 2004;21:

24. Acknowledgements Patients and families of patients with NF
Dr. Bruce Korf
Dr. Ludwine Messiaen
Dr. Amy Theos
Christina Barger
DF and SDRC
CTF