NF1 is inherited in an autosomal dominant fashion with full penetrance and variable expression.³,⁴ The gene responsible for NF1 is an unusually long tumor suppressor gene spanning a length of over 280 Kb of genomic DNA on the long arm of chromosome 17 (17q11.2).¹,²,³,⁴ Because of this unusual length, almost 1500 mutations have been identified in the gene so far,⁴ with approximately half of these mutations being de novo.³,⁴ The NF1 gene codes for a protein called neurofibromin, which during embryonic and fetal life is involved in the differentiation of neural crest-derived cells. Neurofibromin has significant homology to GTPase-activating proteins, which in turn are negative regulators of the RAS-MAPK signal transduction pathway. Ras proteins are signaling molecules involved in physiologic control of cellular proliferation, as well as several pathological processes such as cancer. When the NF1 gene mutates, this results in the loss of neurofibromin function, which in turn reduces GTPase activity within the cell, and therefore results in an overall increase in active Ras proteins leading to unchecked cellular proliferation and possibly cancers. Therefore, NF1 is a cancer predisposition syndrome, and NF1 individuals are at a greater risk than the general population for developing malignancies.⁵,⁶ Because NF1 was the first syndrome to be associated with a germline mutation in the RAS pathway, NF1 is considered by some researchers as belonging to a large genetic family called the RASopathies, which are a well-studied group of medical genetic syndromes caused by germline mutations in genes that encode the components or regulators of the RAS-MAPK pathway.⁴,⁵,⁶

NF1 is one of the most frequently seen neurocutaneous syndromes with a reported incidence between 1/2300-1/3500 live births.⁷,⁸ The clinical presentation which usually involves the skin and the nervous system is remarkably variable with some patients having very few manifestations, whereas others are seriously affected.¹,²,⁹,¹⁰

PN is the most common benign peripheral nerve tumor occurring in the eyelid and typically tracks along the peripheral branches of the trigeminal nerve.¹,² They can assume massive sizes, which may cause significant visual compromise, as well as placing a substantial psychological burden on the patient. PN, which usually occurs as part of the typical constellation of signs and symptoms of NF1, may affect up to 20% of NF1 patients.¹¹,¹² Contrary to some textbooks that emphasize that PN is practically diagnostic of NF1, PN is no longer considered pathognomonic of the disease.¹³ This is because a variant of NF1 may affect the periorbital region in an isolated segmental manner without the other National Institutes of Health (NIH) stigmata of the disease.¹³,¹⁴ exclusively affects the orbital region.¹³ This so-called orbitotemporal variant or segmental NF is reportedly more common in females, and an NF1 gene mutation may be absent.¹³,¹⁵,¹⁶,¹⁷
To settle the argument whether this is a segmental form of NF1 or an entirely separate entity¹³,¹⁷ requires that tumor tissue from the periorbital region in this subset of patients be directly investigated for this mutation.¹³

For reasons that are not yet clear, PN is usually a unilateral disease,¹⁸ but bilateral cases have been reported.⁹,¹² PN in the periorbital region typically assumes a more aggressive course than neurofibromas elsewhere in the body, for reasons that are yet known, this aggressive behavior does seem to level off as the patient matures.¹²,¹⁸ Upper eyelid involvement is usually full thickness extending to the conjunctiva in more than one-half of the patients.⁹ The tarsus and the levator aponeurosis are also significantly involved (Figure 93.1).¹⁹ Ptosis initially occurs due to the mechanical “weight” of the plexiform eyelid lesion even in the presence of good levator muscle function. However, as the neurofibroma enlarges, extensive infiltration of the levator and its aponeurosis may result in distortion of the muscle and disinsertion of its aponeurosis, with impairment of levator function.¹⁹ Initially, the temporal part of the upper eyelid is more infiltrated, resulting in a typical early S-shaped deformity (Figure 93.2).¹,⁹,¹⁸ As the disease progresses, the entire eyelid becomes infiltrated, and the temporal region beyond the eyelid becomes extensively involved with occasional involvement of the entire lateral face. Exclusive involvement of the lower eyelid is extremely rare (Figure 93.3), although combined involvement of the upper and lower eyelids is not uncommon (Figure 93.4).⁹ Lateral and medial canthal malpositions are commonly associated with PN with a reported incidence between 50%-60%,⁹,¹⁸ although predictably lateral canthal involvement always precedes medial canthal malposition.²⁰ Although NF1 often causes vision loss secondary to optic pathway gliomas, it should be noted that decreased visual acuity in NF1 is multifactorial, and PN of the eyelid and orbit can independently cause significant visual morbidity secondary to deprivational amblyopia.² A recent study showed that more than three-fourths of patients with unilateral PN have a visual acuity less than 20/60.¹²