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.

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

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

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

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;105:608-614

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

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

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?

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

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

CALM 1 – Sun Exposure

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

CALM 1(b) – Homogeneity

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

CALM 2 – Results

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

Skin Neurofibromas

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

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

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

Laser Scanner “La guillotine”

Neurofibroma Research Study

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;21:97-101.

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