5.5Genetics

5.5.1 The NF1 Gene

Neurofibromatosis type 1 is caused by a germline mutation in the NF1 gene on chromosome 17q11.2. The gene is autosomal dominant. Most NF1 patients are born with one intact and one defective allele from a germline mutation. When a “second hit” occurs to the intact allele in somatic cells, those cells become vulnerable to tumor growth [48]. Roughly 50% of newly diagnosed cases of NF1, however, occur in patients with no known family history of NF and are presumed new mutations [45]. An estimated 5% of individuals with NF1 have a more severe phenotype due to a complete deletion of the NF1 gene. Genetic testing is now able to detect nearly 95% of all cases. (A publicly funded posting of labs that test for NF1 is available at www.genetests.org.) The protein product of the NF1 gene is neurofibromin. This is a guanosine triphosphatase-activating protein for Ras (a component of the signal transduction pathway for cell growth initiation). It has been shown that the loss of neurofibromin leads to the unsuppressed activity of the intracellular protein Ras with increased cell growth [9]. Neurofibromin has also been suggested to play a role in the tumor suppressor gene TSC2 as well as the growth pathway mTOR [21].

5.5.2 Overlapping NF1-Like Phenotype (SPRED1)

SPRED1 is a newly discovered gene with an acquired mutation that can lead to a NF1 clinical presentation without the loss of the neurofibromin gene. The SPRED1 gene is a member of the SPROUTY/SPRED family of proteins that act as negative regulators of Ras intracellular signaling [40]. The first description of this autosomal

dominant disorder was made in 2007 in a patient with café-au-lait spots, axillary freckling, and macrocephaly [5]. A report found the SPRED1 mutation in 5% (3/61) of patients with the NF1 phenotype but with no identifiable NF1 mutation [40]. This publication underscores our incomplete understanding of the determinative biologic factors in patients who present with the constellation of clinical findings associated with NF1.

Figure 5.4 depicts a patient with a lower eyelid neurofibroma and an ispilateral sphenoid wing dysplasia but without any other characteristic findings of NF1. Genetic testing was positive for the SPRED1 mutation in this patient but negative for the NF1 gene mutation.

Summary for the Clinician

■Orbitofacial neurofibromas is an accurate term to describe the multi-focal location of these tumors in relation to the eye.

■Neurofibromas can occur as localized, plexiform, or diffuse, although the last two are more common in NF1.

■OPGs should be considered proliferating tumors and not hamartomas.

■Remission is most commonly used to describe a positive response to medical therapy.

■Recurrence of tumor describes evidence of tumor after an apparent tumor-free period.

■Progression of tumor describes growth of an existing mass.

■NF1 is caused by a mutation to the neurofibromin gene; however, the newly discovered SPRED1 mutation can cause a NF1-like phenotype without an abnormal neurofibromin gene.