Natural History and Biology of Skin Neurofibromas in Neurofibromatosis Type 1

This protocol results from a funded 2005 Bench-to-Bedside Award and explores the genetic
basis of disease severity in neurofibromatosis type 1 (NF1) and the evaluation of three
methods to measure disease progression of dermal neurofibromas. NF1 is a common multisystem
genetic disorder associated with the development of benign and malignant tumors, primarily of
the nervous system. NF1 is 100% penetrant and features variable expressivity and limited
phenotype/genotype correlation. No standard treatment other than surgery exists for most
NF1-associated tumors. Many aspects of the natural history of NF1-associated tumors

are not fully characterized and require investigation to assess the effects of potential new
treatments, in future clinical trials. The development of medical treatments for
NF1-associated tumors is an important goal given their morbidity and the lack of non-surgical
treatment options. The ability to predict the ultimate severity of disease would have a
significant impact on the management and treatment of individuals with NF1.

Sorafenib (BAY 43-9006) is a novel, orally bioavailable agent that targets downstream
effectors in the Ras signaling pathway (a key dysregulated pathway in NF1). It has thus a
strong scientific rationale for evaluation in NF1 related tumors. Dermal neurofibromas occur
in nearly every individual with NF1, and are a significant cosmetic problem and a major cause
of morbidity. This protocol will 1) quantify the growth of dermal neurofibromas in NF1 with 3
different imaging modalities 2) use an innovative gene expression method to

identify genetic modifiers of dermal neurofibroma burden, and 3) evaluate dermal
neurofibromas and normal skin for the presence of targets of sorafenib. Successful validation
of reliable quantitative imaging methods of dermal neurofibroma growth is a logical
prerequisite to subsequent clinical trials with medical treatments, which will evaluate the
effect of new agents on the growth rate of dermal neurofibromas. Identification of genetic
modifiers may permit prediction of ultimate tumor burden. Evaluation of targets of new agents
in dermal neurofibromas will allow for more rationale drug development for NF1. Given the
paucity of protocols for adults with NF1 and dermal neurofibromas, this study will likely
generate great interest among affected individuals and have rapid accrual.

-INCLUSION CRITERIA - GROUP A INDIVIDUALS:

1. Clinical diagnosis of NF1. In order to meet the diagnosis of NF1 individuals must have
2 of the diagnostic criteria listed below:

- Six or more cafe-au-lait macules (greater than or equal to 0.5 cm in prepubertal
subjects or greater than or equal to 1.5 cm in postpubertal subjects)

- Freckling in the axilla or groin

- A tumor of the optic pathway

- Two or more Lisch nodules

- A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or
thinning of long bone cortex)

- A plexiform neurofibroma or two or more neurofibromas

- A first-degree relative with NF1 by the above criteria

We may request the medical records of potential enrollees for our review. Ideally,
individuals will have been evaluated by a geneticist and a definitive diagnosis made.
However given the unique, familial (and often unmistakable features) of NF1 it is
likely the diagnosis can be reliably made by a non-geneticist.

2. Age at study entry: 20- 50 years (inclusive)

3. Identification of a physician who will be responsible for follow-up care, if needed

4. Ability and willingness to travel to the NIH Clinical Center or University of Alabama
at Birmingham Alabama for multiple evaluations

5. Ability and willingness of both biologic parents to provide a blood (or saliva) sample

6. Must have at least one dermal neurofibroma amenable to excisional biopsy. Preferably
the neurofibroma will be on the thorax or abdomen and be at least the size of a pencil
eraser.

INCLUSION CRITERIA - GROUP B INDIVIDUALS:

1. Biological parents (either affected or unaffected) of Group A individuals

2. Willingness to donate a blood or saliva sample for genotyping

3. Willing to undergo a brief skin and eye exam at the NIH CC (to rule out NF1) or
University of Alabama, if accompanying adult children

EXCLUSION CRITERIA - GROUP A INDIVIDUALS

MEDICAL INCLUSIONS:

1. Any history of administration (or current use) of radiation therapy, chemotherapeutic
agents or biologic agents (experimental or not) that resulted in a documented
significant change in dermal neurofibroma tumor burden or growth.

2. Patients with probable segmental or mosaic NF1 will be excluded from study
participation and medical records may be reviewed prior to enrollment for this
determination.

3. A history of administration of medications within 6 months of study entry that might
reasonably be expected to alter the natural history of tumor growth (examples include
pirfenidone, interferon, farnesyl transferase inhibitor (FTI), MTX/VBL, thalidomide,
growth hormone) or cause significant changes in gene expression profile.

4. Known or suspected untreated bleeding diathesis or platelet disorder that would
preclude safe and successful dermal neurofibroma and skin biopsy. Patients prescribed
aspirin or other known/suspected agent that interferes with platelet function may also
be excluded if they cannot safely discontinue its use a week ahead of the biopsy.

5. Clinically significant unrelated systemic illness, such as serious infection, hepatic,
renal or other organ dysfunction, which in the judgment of the principal investigator
or associate investigator would compromise the patient's ability to participate in the
study procedures.

6. Inability or unwillingness to tolerate the dermal neurofibroma excision and skin
biopsy or blood draw.

VULNERABLE POPULATIONS EXCLUSIONS

1) Cognitive delay to the extent that conscious sedation is required to obtain the dermal
neurofibroma excision and skin biopsy.

OTHER EXCLUSIONS

1. Biologic parents unable or unwilling to provide a blood (or saliva) sample.

2. Inability to travel to the NIH or to The University of Alabama at Birmingham, AL

3. Individuals refusing an excisional tumor or skin biopsy.