Study of Disease Severity in Adults With Neurofibromatosis Type 1 (NF1)
Condition: Neurofibromatosis Type 1; Legius Syndrome
MeSH terms: Neurofibromatoses; Neurofibromatosis 1; Neurofibroma
Study type: Observational

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.
    

Observational model: Family-Based
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Individuals with the genetic disorder Neurofibromatosis Type 1
      
Keywords: Phenotype; NF1-associated tumors; NF1; EQTL; Modifier Genes; Natural History; Neurofibroma; Neurofibromatosis Type 1