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Variation in Gene Expression in Neurofibromatosis Type 1

2 Years
Not Enrolling
Neurofibromatosis Type I

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Trial Information

Variation in Gene Expression in Neurofibromatosis Type 1

We hypothesize that normal germline variation in gene expression accounts, in part, for
variation in the clinical severity and phenotype of the monogenic disorder neurofibromatosis
type 1 (NF1). The phenotype of NF1 is constituted by a variety of quantifiable features; we
term these features sub-phenotypes . Our main focus is on sub-phenotypes with published
evidence of variation in expression from an inherited component. These include our primary
sub-phenotype of spinal neurofibroma burden (quantified by MRI of spinal neurofibromas) and
the secondary sub-phenotypes of dermal neurofibroma burden, head circumference, number of
Lisch nodules, scoliosis, history of plexiform neurofibromas, and height. Other
sub-phenotypes, as collected by a routine history and physical, will also be evaluated.

According to our hypothesis, the severity of a sub-phenotype will correlate with heritable
differences in the germline expression of certain genes. As an example, consider a spectrum
of individuals affected with the primary sub-phenotype of spinal neurofibroma burden. For
most genes, there will be no relationship of expression level to the number of spinal
neurofibromas. However, some genes will have a direct (or inverse, or other) correlation of
their level of expression and the number of neurofibromas. Such genes would be considered
as candidate modifier genes. The secondary sub-phenotypes will also be analyzed in a
similar way. To limit false positives, candidate genes will then be tested for association
(using the transmission/disequilibrium test, TDT) with the appropriate sub-phenotype.

Recruitment will be focused on identifying individuals with a range of severity of the
primary sub-phenotype, spinal neurofibroma burden. We will primarily recruit post-pubertal
individuals who meet the 1988 NIH criteria for neurofibromatosis type 1 (NIH Consensus
Development Conference 1988). We will exclude those with recognized segmental or mosaic
NF1. The rate of cutaneous neurofibroma growth and number is known to vary widely; these
tumors typically appear in adolescence. For this reason we will ascertain patients after
puberty. We expect most individuals to be 18 years or older, but will also accept
post-pubertal pediatric patients (and use a hand film to demonstrate bone age). Parents
(whether affected or not) are critical when using family-based tests of association (like
the TDT) and tests of linkage and will also be recruited.

Tests of association with the TDT require trios (mother, father, proband). Multiple trios
can be derived from a single family, if there are multiple affected individuals within the
family. We set a recruitment goal of 100 trios and a ceiling of 1500 individuals (500
affected individuals, plus 1000 parents or additional sibs in about 400 families).

In the interest of improving care for people living with NF1, this protocol also seeks to

characterize, at the PI's discretion, individuals with unique or under-recognized features
of NF1 as well as individuals with NF1-like phenotypes, including those patients with a
known or suspected RAS pathway disorder.

Inclusion Criteria


Group A: All affected individuals in a family who are post-pubertal male and female
individuals and who meet the 1988 NIH criteria for neurofibromatosis type 1 (NIH Consensus
Development Conference 1988).

Group B: Unaffected individuals greater than 2 years of age who are relatives of
participants (especially parents, but also siblings) are eligible to enroll and are
critical to the success of the study. These individuals may be of any gender and
ethnicity. If the individual is pre-pubertal, s/he must have a brief evaluation at the NIH
Clinical Center (abbreviated medical history and skin and eye exam) to ensure s/he is not
affected with NF1.

Group C: individuals with unique or under-recognized features of NF1 of any age, gender
or ethnicity and must have a correct clinical diagnosis of NF1 (NIH Consensus Development
Conference 1988). all Group C participants enrolling in the study identify a physician
who will be responsible for follow-up care so this can be arranged (if needed) at the
conclusion of the evaluation at NIH.

For healthy normal volunteers used for MRI imaging of the spine, we will aim to recruit
one male and one female from each of 5 decades (18-30 years, 31-40 years, 41-50 years,
51-60 years, 61-70 years). These individuals may be of any ethnicity.

Additional requirements include:

1. If female and of child-bearing age, must be willing to have a serum pregnancy test
(HCG) and

2. Willingness to undergo a brief, focused history and physical exam to rule out occult
spine pathology and to verify there are no contra-indications to spinal MRI imaging.



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 spinal neurofibroma tumor burden or growth.

2. Any history of administration (or current use) of medication 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.

3. Any history of surgery to significantly debulk spinal neurofibromas

4. Pregnancy/Lactation. If an affected pregnant or lactating woman is eligible for
participation, we will request that she enroll after the conclusion of the pregnancy
or lactation.

5. Cognitive delay in an adult or minor to the extent that sedation is required to
obtain MRI.

6. Presence or suspected presence of hardware (Harrington rods) or metallic objects
(e.g. shrapnel, aneurysm clips) or history of exposure to such objects (e.g. welding)
that preclude MRI imaging.

7. Inability or unwillingness to tolerate a 1-hour (or more) MRI protocol.

8. Patients will be excluded if they cannot travel to the NIH because of their medical
condition OR are less than 2 years of age. The PI may decline to enroll a patient for
other reasons.


1) A non-affected pregnant or lactating woman in a family for whom LCL immortalization
will not be performed may participate. However, if she is a member of a multi-affected
family (and thus her blood will be used to prepare LCLs) we will request that she donate a
blood sample at the conclusion of her pregnancy or upon the weaning of her child.


1) Less than 2 years of age.


1. Pregnancy or lactation (a serum HCG level will be drawn on all child-bearing age
women). Women unwilling to have a serum pregnancy test cannot participate.

2. Any history of spine surgery or significant spinal disease (severe arthritis,
autoimmune disorders, severe scoliosis, kyphosis or lordosis, cancer, NF1, NF2, or

3. Any active spine-related complaints: e.g. persistent back pain, radicular symptoms

4. Clinically significant medical condition that, in the opinion of the investigator,
would compromise the patient's safety or affect his/her MRI (e.g., diabetes mellitus,
chronic hypertension, severe anemia, kidney disease, heart disease [angina,
arrhythmias, congestive heart failure]).

5. Previous eye surgery of any kind.

6. Inability to provide informed consent.

7. Permanent tattooed makeup (eyeliner, lip, etc) or general tattoos. Subjects with
tattoos will be excluded if those are in a dangerous location in the body or made
with colors (e.g. dark blue and dark green) whose content in iron cannot be
definitely ruled out by the Investigators.

8. Any non-organic implant or any other device such as: cardiac pacemaker, insulin
infusion pump, implanted drug infusion device, cochlear, otologic, or ear implant,
transdermal medication patch (Nitro, hormones) that may cause problems if removed
even temporarily, any metallic implants or objects, body piercing(s), bone/joint pin,
screw, nail, plate, wire sutures or surgical staples, shunt.

9. Cerebral or other aneurysm clips.

10. Shrapnel or other metal imbedded in the subject's body (such as from war wounds or

11. Previous work in metal fields or with machines that may have left any metallic
fragments in or near the subject's eyes.

12. A severe auto accident in the past so if it is uncertain whether any metal may still
be imbedded in the subject's body.

13. Any psychological contraindications for MRI (e.g., suffer from claustrophobia). This
will be assessed at the time when the medical history will be collected.

14. Any contraindications to having study procedures done.

15. Dental work such as crowns or bridges with indeterminate metals

16. The PI may decline to enroll a patient for other reasons.

Type of Study:


Study Design:


Principal Investigator

Douglas R Stewart, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

May 2005

Completion Date:

Related Keywords:

  • Neurofibromatosis Type I
  • Genetic Modifiers
  • Genotype
  • Phenotype
  • Neurofibroma
  • Single Nucleotide Polymorphism (SNP)
  • Neurofibromatosis Type 1
  • Pediatrics and Adults
  • NF1
  • Neurofibromatoses
  • Neurofibromatosis 1
  • Osteitis Fibrosa Cystica



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892