Lisch nodules (melanocytic hamartomas) are dome-shaped, discrete lesions on the anterior surface of the iris or in the angle, usually bilateral. They are usually orange-brown (Fig. 65.1), appearing darker than blue irides but paler than brown irides (Fig. 65.2). Most are round and evenly distributed on the iris. Their size varies from a pinpoint to involvement of a segment of iris, sometimes confluent. In NF1, they are present in one-third of 2.5-year-olds, half of 5-year-olds, three-quarters of 15-year-olds, and almost all adults over 30.³ They occur earlier than neurofibromas and are, therefore, a useful marker for NF1. They need to be distinguished from iris nevi.

Fig. 65.1 Multiple Lisch nodules in neurofibromatosis.

Fig. 65.2 (A) In brown irides, Lisch nodules appear light brown. (Patient of Dr. Shabana Chaudhry.) (B) Lisch nodules may be difficult to see in brown irides.

Anterior segment and uvea

Rarely, congenital glaucoma with buphthalmos occurs in NF1, often associated with an ipsilateral upper lid plexiform neurofibroma. Congenital ectropion uveae (Fig. 65.3), iris heterochromia, angle abnormalities, and posterior embryotoxon may predispose to later onset glaucoma. Cataract is not a feature of NF1. Pigmentary hamartomas (choroidal nevi) may involve the posterior uveal tract in up to 35%.

Fig. 65.3 Ectropion uveae, another iris abnormality occurring in NF1.

(Patient of Dr. Andrew McCormick, University of British Columbia.)

Skin, lids and orbits

Café-au-lait spots are hyperpigmented macular skin lesions, mostly present at birth and all appear by 1 year, enlarging at puberty. Common on the trunk, they are absent from the scalp, eyebrows, palms, and soles (Fig. 65.4). Histologically, there is melanocytic hyperplasia with increased pigmentation in the basal layer of the epidermis.

Fig. 65.4 Café-au-lait patches as well as multiple axillary freckles in a 14 year old boy.

Neurofibromas are present in 30–50% of NF1 patients.⁴ They are network-like tumor growths involving multiple fascicles of nerve(s); four types are recognized (Table 65.1). The presence and growth pattern of neurofibromas is age related; in infancy and early childhood, diffuse plexiform neurofibromas are most active giving rise to cosmetic and visual problems within the orbit. Cutaneous or subcutaneous neurofibromas develop and grow fastest at puberty, the late teens, and during pregnancy. There is a lifelong risk of malignant transformation with poor prognosis for 5-year survival.⁵

Table 65.1 – Neurofibroma clinical features ⁴

Neurofibroma types	Location	Clinical signs
Discrete cutaneous	Epidermis and dermis	Moves with skin, blueish tinge
Subcutaneous	Deep to dermis	Skin moves over, firm and rounded feel, located along peripheral nerves
Nodular plexiform	Localized interdigitation with normal tissues	“Bag of worms” feel (Figs 65.5, 65.6)
Diffuse plexiform	Infiltrate widely and deeply	Smooth, slightly irregular skin thickening

Fig. 65.5 Upper lid plexiform neurofibroma.

(Patient of the University of Sydney.)

Fig. 65.6 The worm-like consistency of an orbital plexiform neurofibroma can be seen.

(Patient of the University of British Columbia.)

Complete surgical resection of plexiform neurofibromas is difficult due to their large size, location, local invasiveness, or involvement of critical peripheral nerves. Regrowth following subtotal resection is common. Chemotherapy is not effective. Promising clinical trials with biologic agents are underway.⁶

Skeletal anomalies

Hypoplasia of the greater and lesser spenoid wings and widening of the superior orbital fissure may occur. Other osseous abnormalities include abnormal vertebrae, scoliosis, pseudoarthrosis of long bones, and subperiosteal changes (Fig. 65.7). Neurofibromas may interfere with cranial nerve function.

Fig. 65.7 Sphenoid bone dysplasia. (A) Axial CT scan showing absence of greater wing of sphenoid. (B) Plain skull X-ray showing loss of right sphenoid.

Optic disk and central nervous system

Optic pathway gliomas are a significant cause of visual morbidity (see Chapter 23). Optic disk swelling (Fig. 65.8), strabismus (Fig. 65.9), or pallor suggests optic nerve or chiasmal glioma. Retinal manifestations are rare in NF1. The commonest consequence of NF1 in childhood and a major concern of parents is cognitive impairment. Overt mental retardation is rare, but a wide range of learning disabilities, academic underachievement, and behavioral problems may occur.

Fig. 65.8 Girl with neurofibromatosis. (A) Right optic nerve glioma, proptosis, and sensory exotropia due to (B) optic atrophy.

Fig. 65.9 Optic nerve glioma. (A) This 13-month-old girl presented with a history of intermittent exotropia since age 6 months, increasing numbers of café-au-lait spots and increasing proptosis on the left side. She appeared to be blind on the left. (B) T2-weighted MRI showed a fusiform tumor of the optic nerve extending up to and involving the chiasm.

Other systems

Tumors of the spinal cord, sympathetic nerves, and adrenals may occur. The patient may present with malignant hypertension from pheochromocytoma. There may be multiple neurofibromas of the gastrointestinal tract.

Neurofibromatosis type 2

Neurofibromatosis type 2 (NF2) affects 1 in 35 000 live births and is characterized by bilateral vestibular schwannomas, multiple central nervous system (CNS) tumors, cataracts, and retinal abnormalities. The diagnostic criteria for NF2 are shown in Box 65.2. Two patterns of presentation exist. Mild disease presents late (> 25 years), with few tumors other than bilateral vestibular schwannoma, and slow progression. Those with severe disease have onset before age 25, multiple CNS tumors (at least two of one type), and rapid progression, severe handicap or death before reproductive age. Treatment is multidisciplinary because of the complexities of the multiple and progressive lesions.⁷

Box 65.2

Revised diagnostic criteria (Manchester) for NF2

NF2 may be diagnosed in any one of the following situations:

• A. Bilateral vestibular schwannomas

• B. First-degree family relative with NF2 and either unilateral vestibular schwannoma or any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities

• C. Unilateral vestibular schwannoma and any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities

• D. Multiple meningiomas (two or more) and unilateral vestibular schwannoma or any two of: schwannoma, glioma, neurofibroma, cataract

In the Manchester criteria, “any two of” refers to two individual tumors (not different types) or cataract.

Genetics

NF2 is an autosomal dominant condition; half the cases are sporadic mutations. There is an unusually high rate of somatic mosaics (mutation takes place after conception, resulting in two separate cell lineages). Tumors develop in susceptible organs (i.e. nervous system, eyes, and skin) from cells that lose function of the wild type (normal) NF2 allele. There is correlation between nonsense and frameshift mutations and the severe early phenotype of NF2.

The NF2 tumor suppressor gene Merlin is localized to the cell membrane–cytoskeletal interface where it indirectly acts through its membrane organization of proteins. Merlin regulates downstream mitogenic signaling pathways. Drugs targeting these pathways (i.e. sorafenib, trastuzumab, lapatinib, LY294002, protein kinase inhibitors, p21-activated kinase inhibitors) and tumor angiogenesis (bevacizumab) are under investigation as potential treatments for NF2.⁷

Systemic findings

The hallmark of NF2 is bilateral vestibular schwannomas (“acoustic neuromas”) which may only be evident on gadolinium-enhanced MRI (see Fig. 65.11C ). The origin of the trigeminal nerve is another frequent intracranial site for schwannomas; they may occur on multiple cranial nerves. Anti-VEGF (vascular endothelial growth factor) therapy improves hearing and stabilizes tumor growth.⁸

Ocular findings

Most of the ophthalmic findings in NF2 (see Box 65.2) are congenital but may become more symptomatic over time.⁹ Visual loss increases morbidity since progressive bilateral hearing loss is so common in this condition.

Anterior segment

The ocular changes of NF2 are early diagnostic markers. 55–87% of affected patients have presenile central posterior subcapsular lens opacities, usually with little effect on vision (Fig. 65.10A,B). Corneal hypoesthesia from trigeminal nerve schwannoma, and decreased tear production, reduced blinking and lagophthalmos from facial nerve palsy may adversely affect the outcome of cataract surgery.

Fig. 65.10 (A) Cortical cataract in a 12-year-old. (B) Posterior subcapsular plaque in a 12-year-old.

Posterior segment

Epiretinal membranes occur in up to 80% of patients with severe NF2. They are translucent, semitranslucent, or whitish gray membranes with prominent whitish edges demarcating their borders. They do not usually cause substantial loss of visual acuity (Fig. 65.11).

Fig. 65.11 (A) Epiretinal membrane in a 14-year-old NF2 patient. Note also papilledema secondary to optic sheath meningioma. (B) OCT scan of epiretinal membrane. Note loss of internal limiting membrane. (c) Bilateral vestibular schwannomas as well as bilateral optic sheath meningiomas in a 14-year-old boy − same patient as in (A) and (B).

(MRI scan courtesy Dr. Mark Dexter, Neurosurgeon.)

Combined retinal and pigment epithelial hamartomas occur in 6−22% of NF2 patients, especially with nonsense mutations.⁹ They are slightly raised masses most frequently in the posterior pole (Fig. 65.12), commonly causing reduced vision. Optic nerve sheath meningiomas, sometimes bilateral, can cause visual loss (see Chapter 23). They may be missed on MRI unless fat suppression techniques are used.