Neurofibromatosis type 1 (NF1) is an autosomal-dominant tumor predisposition syndrome in which affected children are prone to the development of low-grade astrocytic (glial) neoplasms along the optic pathway (optic pathway glioma, OPG). In this regard, 30% of OPGs are found in children with NF1, making NF1 the most common genetic cause for this visual pathway tumor. The protean manifestations and unpredictability of the clinical course of an individual with NF1 often make this complex condition challenging to manage for the practitioner.
Historical depictions of individuals who clearly display manifestations of NF1 can be found in art dating back to as early as the 15th century. Frederick Daniel von Recklinghausen provided the first complete pathologic description of NF1 (1881), reporting both the gross and histologic features, and demonstrating for the first time that the cutaneous masses contained neural elements. Although Crowe (1953) emphasized the importance of the café-au-lait spot in the diagnosis of “von Recklinghausen disease,” the recognition of NF1 as a distinct clinical entity did not occur until 1981. Finally, in 1987 the National Institutes of Health Consensus Development Conference defined the seven diagnostic criteria for NF1, of which two must be present to confirm the diagnosis ( Box 53.1 ).
Two or more of the following must be present to establish the diagnosis of NF1:
Six or more café-au-lait macules >5 mm in prepubertal individuals, or >15 mm in postpubertal individuals
Two or more neurofibromas, or one plexiform neurofibroma
Freckling in the axillary or inguinal region
Two or more Lisch nodules
A distinctive osseous lesion (sphenoid dysplasia or thinning of long bone cortex with or without pseudarthrosis)
A first-degree relative with NF1 by above criteria
Key signs and symptoms of NF1
Café-au-lait spots and intertriginous freckling ( Figure 53.1A )
Café-au-lait spots are flat, pigmented macules, and are generally the first cutaneous manifestation of NF1. Often present at birth, they become apparent during the first few years of life. As many as 97% of children who are eventually diagnosed with NF1 will have six or more café-au-lait spots by the time they are 6 years of age. Patients with greater numbers of café-au-lait spots are not at risk for the development of more severe disease. While freckling is common in sun-exposed areas of individuals without NF1, smaller café-au-lait spots or freckling may be seen in areas not directly exposed to the sun in individuals with NF1, and constitutes the second most common diagnostic criterion found in young children. These freckles typically occur in skinfolds, including the axilla, inguinal creases, submammary regions, and the neck.
Dermal neurofibromas ( Figure 53.1B )
Neurofibromas, the hallmark lesion of NF1, are benign nerve sheath tumors arising from peripheral nerves. These tumors are composed of neoplastic Schwann cells as well as numerous stromal cell types (i.e., mast cells, fibroblasts, and perineural cells). Cutaneous neurofibromas arise from small superficial nerves; they are soft, protrude just above the skin’s surface, and often display a violaceous hue. In contrast, subcutaneous neurofibromas arise from deeper nerves and are generally firm. Deep visceral neurofibromas may cause symptoms by compressing vital structures, such as is seen in spinal cord compression from dorsal root neurofibromas. Although young children may have some neurofibromas, these tumors tend to appear with the onset of puberty and increase in both size and number with advancing age.
Plexiform neurofibromas ( Figure 53.1C )
Although plexiform neurofibromas are histologically similar to dermal neurofibromas, they are clinically quite distinct. They are often present at birth or develop in the first several years of life, undergoing a phase of rapid growth during childhood. Although these tumors are generally soft, the observer can often feel multiple firmer thickened nerves within the tumor, described as a “bag of worms.” Overlying hyperpigmentation or fine hair growth may be a clue to the presence of an underlying plexiform neurofibroma. Often arising from branches of major nerves, they can become large and cause significant dysfunction. Plexiform neurofibromas involving the eyelid or orbit may lead to visual loss from associated glaucoma, amblyopia secondary to proptosis, or optic nerve damage. Internal plexiform neurofibromas can cause morbidity as a result of spinal cord compression, erosion of contiguous bone, or ureteral/bladder outlet obstruction.
Lisch nodules ( Figure 53.1D )
Lisch nodules are dome-shaped melanocytic hamartomas of the iris, and are virtually pathognomonic of NF1. Not associated with any visual abnormalities, they are present in 90–95% of adults with NF1. They are best visualized using a slit lamp by an experienced ophthalmologist.
Optic pathway gliomas
Although children 6 years of age and younger with NF1 are at greatest risk for the development of an OPG, new symptomatic OPGs may also arise in older children and adults. If neuroimaging is performed on all children with NF1 at the time of diagnosis, 15–20% of these children will harbor an OPG. However, only half of these tumors will ever become symptomatic, giving an overall incidence of symptomatic OPGs of 7%.
NF1-associated OPGs are usually to the anterior visual pathway, including the intraorbital optic nerve, intracranial optic nerve, and the optic chiasm ( Figure 53.2 ). In contrast, sporadic OPGs not associated with NF1 commonly involve the optic tracts and postchiasmatic optic radiations as well. Bilateral intraorbital OPGs are virtually pathognomonic of NF1 ( Figure 53.3A ).
Symptomatic OPGs may become apparent in one of several ways. Approximately 30% of such tumors will present with the rapid onset of unilateral proptosis and significantly decreased visual acuity secondary to large intraorbital tumors. An additional 30% of patients will have an abnormal ophthalmologic examination without any visual symptoms, since young children rarely complain of gradual visual loss. Abnormal ophthalmologic signs may include optic nerve atrophy or pallor, an afferent pupillary defect, uncorrectable decreased visual acuity, strabismus, or papilledema. The remaining 40% of children will present with signs of precocious puberty, usually with accelerated linear growth. Such children invariably harbor chiasmatic tumors which can affect the hypothalamic–pituitary–gonadal axis ( Figure 53.3B ). Thus, it is essential that all young children with NF1 have annual assessments of linear growth plotted on standardized pediatric growth charts.
Natural history of OPG
Predicting the natural history of an individual OPG is impossible. For example, rapidly progressive intraorbital tumors which cause proptosis and significant visual loss may stop growing following initial presentation. While progressive disease following the diagnosis of a symptomatic OPG occurs in 35–52% of cases, OPGs found by screening neuroimaging of asymptomatic individuals with NF1 rarely progress. Most importantly, the natural history of NF1-associated OPGs is markedly different from that of sporadic OPG. The latter are significantly more likely to progress radiographically and clinically, leading to the development of increased intracranial pressure and hydrocephalus with substantially greater ophthalmologic morbidity.
Diagnostic evaluation of asymptomatic children with NF1
All young children with NF1 should undergo complete yearly ophthalmologic examinations in order to identify the earliest manifestations of a symptomatic OPG. Complete examinations including ocular alignment and rotations, assessment of color vision, pupillary light response, refractive status, and fundoscopic evaluation should be performed. Visual acuity should be measured using age-appropriate testing (i.e., preferential looking tests in infants, Lea figure, or HOTV matching in preliterate children, Snellen charts in older children). Routine measurement of visual fields is unnecessary as clinically important visual field compromise without concomitant loss of visual acuity is rare. There is no reliable evidence supporting the routine use of visual evoked potentials in the diagnosis of NF1-associated OPG.
There has been considerable debate as to the role of neuroimaging of asymptomatic children with NF1. Routine “screening” neuroimaging would be important if it led to the early detection of OPG which, in turn, led to significantly decreased ophthalmologic morbidity. However, there are substantial data showing that such a strategy would fail; in previous studies, many tumors were detected that never progressed and some children developed symptomatic OPG after a normal visual screening examination. Thus, there is no conclusive evidence that the early detection of OPGs leads to improved outcome. For these reasons, screening “baseline” neuroimaging of asymptomatic children with NF1 is not recommended.
Follow-up of an asymptomatic OPG
Once an asymptomatic NF1-associated OPG has been identified, close follow-up is warranted, as the natural history of an individual tumor cannot be predicted. Generally, ophthalmologic examinations should be performed every 3 months during the first year following diagnosis. Magnetic resonance imaging should also be performed at frequent intervals; the exact protocols vary among institutions. As the child gets older without evidence of either clinical or radiographic progression, the intervals between examinations can be progressively lengthened.
There are scant data as to what constitutes sufficient clinical or radiographic progression to warrant treatment. Radiographic progression without a concomitant change in the child’s visual examination may not be sufficiently compelling to mandate treatment. Additionally, the appearance of clinical signs, such as the development of precocious puberty, does not constitute in itself a reason for treatment. However, once the decision to undergo treatment has been made, certain truths exist.
There is a limited role for surgery in the management of NF1-associated OPG. Partial removal of an intraorbital optic nerve glioma is usually reserved for cosmetic purposes only. On occasion, surgical decompression of a hypothalamic glioma may be necessary to treat hydrocephalus secondary to third ventricular compression. Biopsy is only recommended in very atypical cases as NF1-associated OPG are most often low-grade juvenile pilocytic astrocytomas. Similarly, radiotherapy in children with NF1 is not recommended, because of the unacceptable neurovascular (cerebral occlusive vasculopathy), endocrinologic, and neuropsychologic sequelae. Moreover, recent evidence suggests that children with NF1 treated with radiation therapy develop secondary brain malignancies later in life.
Chemotherapy has become the mainstay of treatment for NF1-associated OPGs. The most commonly used chemotherapeutic regimen is the combination of carboplatin and vincristine. This combination is effective in controlling the growth of most NF1-associated OPGs, and is typically well tolerated in this age group. Other chemotherapies have also been used; however, there is no consensus on which second-line therapy is most effective for these tumors.
The vast majority of NF1-associated OPGs are classified by the World Health Organization (WHO) as grade I astrocytic neoplasms (pilocytic astrocytomas). Similar to pilocytic astrocytomas arising in other brain regions in individuals with NF1, these low-grade gliomas are characterized by a biphasic histologic pattern of more cellular areas alternating with looser cystic regions. Within the less compact areas, there are Rosenthal fibers (tapered corkscrew-shaped hyaline masses) and eosinophilic granular bodies (globular aggregates). These tumors exhibit low mitotic indices with rare mitoses and occasional hyperchromatic nuclei. Despite their benign nature, pilocytic astrocytomas are rather infiltrative tumors with significant microvascular proliferation and the presence of microglia. Immunohistochemical analyses of these tumors reveal robust staining with glial fibrillary acidic protein antibodies, characteristic of astrocytic neoplasms.
NF1 is caused by a germline mutation in the NF1 gene; however, only 50% of all individuals with NF1 have an affected parent. These individuals without a family history of NF1 represent new mutations, which presumably arise from a mutation in the NF1 during spermatogenesis in the male. Since NF1 is an autosomal-dominant disorder with complete penetrance, the risk of transmitting NF1 is 50% with each pregnancy. Children who inherit a mutated (nonfunctional) copy of the NF1 gene have NF1, yet the clinical manifestations may be variable. In this regard, a child with NF1 with the identical NF1 gene mutation as a parent or sibling can be more severely or more mildly affected. Moreover, there are no obvious genotype–phenotype correlations that predict disease severity, with the exception of children with large chromosomal deletions surrounding the NF1 gene. These children frequently have mental retardation and distinctive facial features, and may be at risk for the development of malignancy. Finally, there are no known environmental risk factors and NF1 has been described in all ethnic and racial groups worldwide.