Study of Disease Severity in Adults With Neurofibromatosis Type 1 (NF1)

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Brief Title

Study of Disease Severity in Adults With Neurofibromatosis Type 1 (NF1)

Official Title

Variation in Gene Expression in Neurofibromatosis Type 1

Brief Summary

      This study may identify genes that predict the seriousness of neurofibromatosis type 1 (NF1).
      Finding these genes may explain why some people with NF1 have more medical problems than
      others. The study will also examine medical problems in NF1 that are rarely seen and are not
      well understood.

      Male and female patients with NF1 who have gone through puberty may be eligible for this
      study, as well as patients of any age who have unique or under-recognized disease features.
      Affected and unaffected family members, including parents, siblings, and more distant
      relatives, may also be enrolled. Candidates are screened with a discussion of medical history
      or review of medical records, or both. Participants undergo the following procedures:

      Patients with NF1

        -  Physical examination and family history

        -  Photographs of the iris of each eye

        -  Photographs of the back, abdomen and thigh to count skin tumors

        -  Photographs of the face and body (with underwear on) to help track growth and appearance

        -  Magnetic resonance imaging (MRI) of the spine (This test uses a magnetic field and radio
           waves to look for tumors and curvature of the spine. The patient lies still in the
           scanner, a narrow cylindrical device, wearing earplugs to muffle loud knocking sounds
           that occur during the scan. A contrast material called gadolinium is injected into a
           vein through a catheter to enhance the images.)

        -  Blood draw for genetic studies

        -  Possibly a skin biopsy (with the use of numbing medicine, removal of a small sample of
           skin tissue) to grow cells in the laboratory

      Patients with NF1 who have unique or under-recognized disease features

        -  Physical examination and family history

        -  Blood draw for genetic studies

        -  Possibly a skin biopsy

        -  Possibly additional tests, such as blood work, x-rays, photographs, MRIs, ultrasounds,
           or other tests

      Unaffected family members

        -  Blood draw for genetic studies

        -  Brief skin and eye examinations

        -  Possibly a skin biopsy for cell culture

      Families are asked to give permission for researchers to recontact them for follow-up
      information, additional blood samples, or follow-up visit.
    

Detailed Description

      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.
    


Study Type

Observational


Primary Outcome

Phenotype individuals and family members affected with NFl by routine history and physical.


Condition

Neurofibromatosis Type 1


Study Arms / Comparison Groups

 Group A
Description:  Affected participants, must have a correct clinical diagnosis of NF1.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

313

Start Date

July 27, 2005



Eligibility Criteria

        -  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.

        EXCLUSION CRITERIA:

        EXCLUSION CRITERIA FOR GROUP A INDIVIDUALS INCLUDE:

          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.

        EXCLUSION CRITERIA FOR GROUP B INDIVIDUALS INCLUDE:

        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.

        EXCLUSION CRITERIA FOR GROUP C INDIVIDUALS INCLUDE:

        1) Less than 2 years of age.

        EXCLUSION CRITERIA FOR HEALTHY, NORMAL VOLUNTEERS INCLUDE:

          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
             schwannomatosis)

          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
             accidents).

         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.
      

Gender

All

Ages

2 Years - 100 Years

Accepts Healthy Volunteers

No

Contacts

Douglas R Stewart, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00111384

Organization ID

050152

Secondary IDs

05-C-0152

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Douglas R Stewart, M.D., Principal Investigator, National Cancer Institute (NCI)


Verification Date

October 4, 2021