Clinical Characteristics

In NF1, the usual presenting signs are cutaneous manifestations. These skin changes include café-au-lait macules, cutaneous neurofibromas, hypopigmented macules, patchy and diffuse areas of hyperpigmentation, juvenile xanthogranulomas, and angiomas. Café-au-lait macules usually are present at birth and range in size from a few millimeters to centimeters [Crowe et al., 1956] (Figure 40-1). They do not significantly increase in number after the first 2 years of life. Six or more café-au-lait macules measuring at least 5 mm across before puberty or 15 mm after puberty constitute one diagnostic criterion for NF1. Rare persons with variant forms of neurofibromatosis, such as spinal neurofibromatosis [Messiaen et al., 2003; Korf et al., 2005], may lack café-au-lait macules, and one rare NF1 gene mutation is associated with café-au-lait macules and no neurofibromas in affected individuals [Upadhyaya et al., 2007]. Individuals with mutation in the SPRED1 gene may also present with multiple café-au-lait macules, skinfold freckles, and macrocephaly, but do not appear to develop neurofibromas or other tumor-related NF1 complications [Brems et al., 2007; Messiaen et al., 2009]. Nevertheless, in a majority of children who present with six or more café-au-lait macules and do not have an alternative diagnosis, signs of NF1 eventually develop [Korf, 1992]. Usually the second sign to appear is skinfold freckling [Crowe, 1964] (Figure 40-2). Freckles begin in the inguinal region in children at 3–4 years of age, and eventually appear in the axillae, at the base of the neck, and in the inframammary region in females. Areas of freckling also can be found over the trunk and extremities. Diffuse, patchy areas of hyperpigmentation also may appear, sometimes overlying plexiform neuromas [Riccardi, 1980]. Areas of hypopigmentation or hypovascularity also may occur. Juvenile xanthogranulomas appear as firm yellowish papules in infants and young children, and eventually regress. Although an association with leukemia has been suggested [Zvulunov, 1996], this has not been verified.

Fig. 40-1 Multiple café-au-lait spots.

Fig. 40-2 Axillary freckling.

Cutaneous neurofibromas are a prominent finding in NF1 and are located in the dermis or adjacent to it (Figure 40-3). They are discrete, soft or firm papules, ranging in size from a few millimeters to several centimeters, can be flat, sessile, or pedunculated, and can be readily impressed into the skin below. Neurofibromas can develop at any time and in any location, and may affect any component of the peripheral nervous system, from the dorsal root ganglion to the terminal nerve twigs. Plexiform neuromas represent tumors that involve a longitudinal section of nerve and can involve multiple branches of a major nerve [Korf, 1999]. Near the surface of the body they can cause thickening and hypertrophy of the skin and soft tissues (Figure 40-4). They may occur deeper in the body and be detected only by imaging [Tonsgard et al., 1998]. Tumors of the orbit or limbs can cause major physical deformity. Plexiform neurofibromas can be congenital lesions, often growing rapidly in the early months of life; they then may remain quiescent for long periods of time or grow unpredictably. The tumors are easily visualized by magnetic resonance imaging (MRI), and display a characteristic “target sign.” Volumetric MRI may be helpful in following their growth [Dombi et al., 2007; Cai et al., 2009]. Neurofibromas originating at the dorsal roots may grow in a dumbbell shape and invade the spinal canal (Figure 40-5], sometimes causing spinal cord compression. The gastrointestinal tract can also be affected by growth of neurofibromas or ganglioneuromas. These tumors can cause intestinal obstruction or bleeding.

Fig. 40-3 Multiple cutaneous neurofibromas.

Fig. 40-4 Truncal plexiform neurofibroma with overlying hyperpigmentation.

Fig. 40-5 Magnetic resonance imaging scan showing bilateral spinal tumors, with displacement of the cord by the larger tumor on the right side of the photo.

Ophthalmologic features of NF1 include Lisch nodules, glaucoma, and optic glioma. Iris Lisch nodules are melanocytic hamartomas that are highly specific to NF1 [Lisch, 1937; Lewis and Riccardi, 1981]. Their appearance is age-dependent, usually beginning at the age of approximately 6 years. Lisch nodules occur in approximately 95 percent of adults with the disorder [Lubs et al., 1991] and are therefore helpful in diagnosis. Glaucoma usually occurs when a plexiform neurofibroma involves the upper eyelid (Figure 40-6) [Morales et al., 2009]. Orbital plexiform neurofibroma, arising from the trigeminal nerve, often is associated with sphenoid dysplasia, and can present with pulsating exophthalmos or enophthalmos [Jacquemin et al., 2002].

Fig. 40-6 Orbital plexiform neurofibroma associated with buphthalmos.

Optic pathway gliomas are found in approximately 15 percent of patients [Lewis et al., 1984]. Most are asymptomatic, but these tumors can manifest with symptoms of decreased visual acuity, visual field defects, or precocious puberty [Listernick et al., 2007]. The glioma can involve the optic nerves, chiasm, optic radiations, and hypothalamus (Figure 40-7); it rarely manifests as the diencephalic syndrome of infancy or precocious puberty. Optic gliomas are pilocytic astrocytomas, but often are slow-growing.

Fig. 40-7 Sagittal magnetic resonance imaging scan of brain showing a glioma of the optic chiasm (arrow).

Aside from optic gliomas, astrocytomas of the cerebrum, brainstem, and cerebellum are the most common intracranial tumors encountered in NF1 [Albers and Gutmann, 2009]. Malignant peripheral nerve sheath tumor occurs in upwards of 8–13 percent of affected persons [Evans et al., 2002]. These manifest with pain or sudden growth, usually within a pre-existing plexiform neurofibroma [D’Agostino, Soule and Miller, 1963]. Various other neoplastic disorders occur more frequently in patients with NF1 than in the general population, including leukemia, especially juvenile myelomonocytic leukemia [Stiller, Chessells and Fitchett, 1994] and pheochromocytoma [Walther et al., 1999a].

Macrocephaly and short stature are common in NF1 and scoliosis has been reported to occur in 10–40 percent of patients [Crawford and Herrera-Soto, 2007]. Scoliosis usually does not develop before the age of 6 years and most commonly involves the thoracic spine. Bowing of the tibia, fibula, and other long bones can be present in early life, with occurrence of spontaneous fractures at the junction of the middle and distal thirds of the bone shaft, resulting in pseudarthrosis [Elefteriou et al., 2009; Stevenson et al., 1999]. Non-ossifying fibromas may occur and can present with pain or fracture [Howlett et al., 1998]. There is also evidence for decreased bone mineral density in children and adults with NF1, which may contribute to an increased risk of fracture [Stevenson et al., 2008; Kuorilehto et al., 2005].

Approximately 50 percent of patients have learning disabilities, with no specific pattern unique to those with NF1 [Hyman, Arthur Shores and North, 2006]. Both verbal and nonverbal disabilities occur, as well as attention-deficit disorder [Mautner et al., 2002] and hypotonia [Souza et al., 2009]. Fewer than 10 percent have mental retardation, and most of these patients have large deletions of the NF1 gene [Kayes et al., 1994]. Seizures occur in approximately 6–10 percent of patients [Korf, Carrazana and Holmes, 1993]. The pathogenesis of the cognitive phenotype is not known. Abnormal cortical architecture and heterotopias have been reported in the brains of some patients with severe cognitive deficits [Rosman and Pearce, 1967]. It has been suggested that the areas of enhanced T2 signal intensity characteristically seen in the brains of children with NF1 (Figure 40-8) may be associated with learning disabilities [Hyman et al., 2007]. These lesions occur in the basal ganglia, brainstem, cerebellum, and internal capsule; tend to disappear with age [Hyman et al., 2003; Ferner et al., 1993]; and are characterized by increased myelin water content and gliosis [DiPaolo et al., 1995].

Fig. 40-8 Area of enhanced T2 signal intensity in cerebellum (arrow).

Vascular anomalies in NF1 include regions of intimal proliferation and fibromuscular changes in small arteries [Friedman et al., 2002]. Renal artery stenosis can lead to hypertension in children [Fossali et al., 2000], and involvement of other vessels can cause vascular insufficiency or hemorrhage as a result of arterial wall dissection [Hinsch et al., 2008]. Stenosis of the internal carotid artery can lead to moyamoya disease and stroke [Cairns and North, 2008], although lesions often are asymptomatic. The stenotic changes can arise spontaneously in children with NF1, but frequently develop after radiation therapy for brain tumors in young children [Kestle, Hoffman and Mock, 1993].

Pathology

Neurofibromas consist of a mixture of cell types, including Schwann cells, fibroblasts, perineurial cells, and mast cells [Pineda, 1965]. They are polyclonal [Fialkow et al., 1971], but genetic studies have confirmed that the “tumor cell” is the Schwann cell [Sherman et al., 2000; Zhu et al., 2002], or in the case of dermal neurofibromas, stem cells referred to as skin-derived precursors [Le et al., 2009]. The other cell types present in the lesion apparently proliferate as a secondary phenomenon, perhaps in response to stimulation by cytokines [Yang et al., 2003]. Mast cells are present in large numbers and have been suspected of being a source of cytokines [Yang et al., 2008]. In plexiform neurofibromas, the pathologic process extends across multiple nerve fascicles instead of occurring at a focal site in a nerve, and may extend across branches of a larger nerve. Malignant peripheral nerve sheath tumor manifests as a malignant tumor of Schwann cell origin, although sometimes rhabdoid elements are present in such tumors [Buck, Mahboubi and Raney, 1977]. Most, if not all, of these neoplasms arise from pre-existing tumors, usually plexiform neurofibromas. The pathology of other NF1-associated lesions is less well understood than that of the neurofibroma.

Genetics

NF1, inherited as an autosomal-dominant trait, has an estimated prevalence of 1 in 3000; about half of cases are new mutations [Crowe, Schull and Neel, 1956; Huson, Harper and Compston, 1988]. The NF1 gene is located at 17q11.2 and encodes a 3818-amino-acid protein referred to as neurofibromin [Cawthon et al., 1990a, b; Viskochil et al., 1990; Wallace et al., 1990]. Neurofibromin is expressed in multiple cell types but is highly expressed in Schwann cells, oligodendrocytes, and neurons [Daston et al., 1992]. The protein includes a functional GTPase-activating protein (GAP) domain that regulates conversion of Ras-guanosine triphosphate to Ras-guanosine diphosphate [Ballester et al., 1990; Xu et al., 1990a, b]. Ras is a membrane-bound intracellular signaling molecule that is activated by complexing with guanosine triphosphate (GTP) on ligand binding to membrane receptor tyrosine kinases. GAP proteins regulate this process by stimulating a GTPase activity that is intrinsic to Ras [Bernards, 2003]. Neurofibromin functions as a tumor suppressor gene with respect to neurofibroma formation [Sherman et al., 2000; Cichowski and Jacks, 2001; Zhu et al., 2002]. The germline mutation of one NF1 allele constitutes the first “hit”; the second hit is a somatic mutation [Upadhyaya et al., 2004] in a Schwann cell that causes that cell to proliferate and attract other cells, such as mast cells, fibroblasts, and perineurial cells, which also proliferate. These cells, being heterozygous for the NF1 mutation, may be hypersensitive to cytokine stimulation [Vogel et al., 1995]. Transformation to malignancy requires additional genetic changes, such as mutation of p53 [Legius et al., 1994]. Biallelic NF1 gene mutation also occurs in melanocytes within café-au-lait macules [Maertens et al., 2007] and in dysplastic bone tissue [Stevenson et al., 2006]. It is unclear whether other dysplastic lesions also occur as a result of a tumor suppressor mechanism, or whether haploinsufficiency of neurofibromin expression itself causes these lesions. Mice rendered heterozygous for an NF1 mutation do display cognitive deficits [Costa et al., 2002], suggesting that haploinsufficiency might account for some of the NF1 phenotype.

NF1 exhibits a wide range of variability of expression and complete penetrance. Mutations are widely scattered across the gene and include a wide variety of mutational mechanisms [Messiaen et al., 2000]. Most of the mutations lead to decreased level of expression of neurofibromin or complete lack of expression. Few genotype–phenotype correlations have been established. Large deletions that include the NF1 gene and multiple contiguous genes over a 1.5-Mb region tend to lead to a particularly severe form of NF1, with mental retardation, early onset of large numbers of neurofibromas, facial dysmorphism, and increased risk of cancer [De Raedt et al., 2003; Kayes et al., 1994; Wu et al., 1995]. Another variant form of neurofibromatosis, familial spinal neurofibromatosis, may represent an additional genotype–phenotype correlation. Persons with this disorder have multiple spinal neurofibromas and subcutaneous tumors but lack skinfold freckling and dermal tumors, and tend to have missense mutations or splicing mutations [Korf, Henson and Stemmer-Rachamimov, 2005]. Individuals with a three-base deletion in exon 17 have only café-au-lait spots and do not develop neurofibromas [Upadhyaya et al., 2007]. Approximately 50 percent of cases of NF1 occur sporadically, as a result of a new mutation of the NF1 gene. Because of the high penetrance of the disorder, unaffected parents of a sporadically affected child have a low risk of recurrence, barring the rare instance of germline mosaicism [Lazaro et al., 1995]. Somatic mosaicism for NF1 may manifest with segmental distribution of features [Tinschert et al., 2000; Vandenbroucke et al., 2004]. Genetic testing for diagnosis of NF1 is available on a clinical basis. It is used to confirm a diagnosis in patients who fulfill only a single diagnostic criterion, to characterize patients with unusual clinical presentations, and to enable prenatal testing. The discovery of mutation in the SPRED1 gene accounting for patients with multiple café-au-lait spots but lacking other features of NF1 [Brems et al., 2007] (now referred to as “Legius syndrome”), provides additional rationale for genetic testing in young children with multiple café-au-lait spots. The majority of mutations are found in the NF1 gene, making it cost-effective to begin with NF1 testing, followed by SPRED1 testing if no NF1 mutation is found [Messiaen et al., 2009].

Management

Treatment of patients with neurofibromatosis is symptomatic. Affected persons should be followed on a regular basis by a physician who is familiar with the disorder to recognize treatable complications early and to provide anticipatory guidance and counseling. Genetic counseling should be provided. Controversy surrounds the use of imaging, especially MRI, in screening patients with NF1. Most of the lesions that will be identified are not amenable to treatment, so such testing may create needless anxiety, and in children the procedure carries the risks associated with sedation. The value of the “baseline” examination is questionable because most of the lesions of NF1 are slow-growing and will be followed both clinically and by imaging once they come to attention [Listernick et al., 1994]. Current consensus guidelines do not recommend routine imaging [Gutmann et al., 1997], although care should be individualized for specific clinical needs.

Neurofibromas of the peripheral nerves need not be removed unless they are subject to repeated irritation and trauma or develop malignant change. Some plexiform neuromas can be removed for cosmetic reasons, although complete resection is difficult and regrowth is common [Needle et al., 1997]. Malignant tumors are managed with appropriate neurosurgical measures, radiation therapy, and chemotherapy. Optic gliomas tend to behave in an indolent manner and therefore are followed clinically without treatment in asymptomatic children [Listernick et al., 2007]. Symptomatic tumors most often are treated with chemotherapy [Packer et al., 1997]; radiation therapy may be associated with second malignant tumors [Sharif et al., 2006] or moyamoya disease [Desai et al., 2006; Kestle, Hoffman and Mock, 1993]. Malignant peripheral nerve sheath tumors tend to be highly malignant, so early diagnosis is essential [Evans et al., 2002]. Patients with unexplained pain or growth of a neurofibroma should be evaluated, with consideration of biopsy. Positron emission tomography (PET) scanning may be helpful in distinguishing a malignant peripheral nerve sheath tumor from plexiform neurofibroma [Ferner et al., 2000; Karabatsou et al., 2009; Warbey et al., 2009].

Clinical trials of drugs to treat specific complications are on-going. These include the use of statins to treat learning disabilities [Krab et al., 2008] and several experimental treatments for neurofibromas [Babovic-Vuksanovic et al., 2007; Gupta et al., 2003; Packer and Rosser, 2002; Packer et al., 2002].

Clinical Characteristics and Pathology

Diagnostic criteria for NF2 are presented in Box 40-3 [Gutmann et al., 1997; Stumpf, 1988; Baser et al., 2002]. The defining feature of NF2 is the occurrence of bilateral vestibular schwannomas. Age at onset is highly variable, ranging from early childhood to the seventh decade and beyond [Evans 1999; Mautner et al., 1993]. In view of this variability in age at onset of vestibular tumors, NF2 also should be considered in patients with early onset of associated tumors or those with combinations of associated tumors.

Box 40-3 Diagnostic Criteria for Neurofibromatosis 2

Confirmed NF2*

Bilateral vestibular schwannomas

or

A first-degree relative with NF2

and either

Unilateral vestibular schwannoma before age 30 years

or any two of

Meningioma, schwannoma, ependymoma, juvenile lens opacity

Presumptive NF2

Unilateral vestibular schwannoma before age 30 years and at least one of: meningioma, schwannoma, ependymoma, juvenile lens opacity

or

Two or more meningiomas and unilateral vestibular schwannoma before age 30 years or at least one of: meningioma, schwannoma, ependymoma, juvenile lens opacity

Manchester Criteria^†

Bilateral vestibular schwannomas

or

A first-degree relative with NF2

and either

Unilateral vestibular schwannoma or any two of: meningioma, schwannoma, ependymoma, neurofibroma, posterior subcapsular lenticular opacity

or

Unilateral vestibular schwannoma and any two of: meningioma, schwannoma, ependymoma, neurofibroma, posterior subcapsularlenticular opacity

or

Two or more meningiomas and unilateral vestibular schwannoma or any two of: meningioma, schwannoma, ependymoma, neurofibroma, posterior subcapsular lenticular opacity

^* Gutmann DH et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 1997;278: 51–57.

^† Baser ME et al. Evaluation of clinical diagnostic criteria for neurofibromatosis 2. Neurology 2002;59(11):1759–1765.)

(Based on

Vestibular schwannomas commonly manifest with tinnitus and/or hearing loss, and may cause problems with balance [Evans, 1999]. Audiology and auditory brainstem-evoked response testing can be helpful, but definitive diagnosis is based on MRI findings (Figure 40-9). Early tumors may be confined to the internal auditory canal and require careful search with thin MRI slices to be detected. Schwannomas can occur along any other cranial nerve, the fifth being most common after the eighth. Schwannomas also may occur along spinal nerves, with the potential for causing radiculopathy or cord compression, or along peripheral nerves. In some patients, a polyneuropathy develops as a result of Schwann cell proliferation around peripheral nerves [Gijtenbeek et al., 2001; Hagel et al., 2002]. Dermal schwannomas appear as plaquelike lesions, often with associated hair growth. Café-au-lait macules are not a reliable indicator of NF2, unlike in NF1 [Mautner et al., 1997]. Other major central nervous system tumors associated with NF2 are meningiomas and ependymomas. Multiple meningiomas may not be surgically resectable and can be responsible for significant morbidity. Virtually the entire NF2 phenotype is characterized by proliferative lesions; the one exception is the occurrence of posterior subcapsular cataracts or cortical wedge opacities [Pearson-Webb et al., 1986].

Fig. 40-9 Magnetic resonance imaging scan of brain from a person with NF2 showing a meningioma (arrow 1) and two vestibular schwannomas (arrows 2 and 3).

The tumor indicated by arrow 3 has been partially resected.

Genetics

NF2 is transmitted as an autosomal-dominant trait with complete penetrance and variable expression. Prevalence is estimated at approximately 1 in 60,000, and birth incidence at 1 in 30,000 [Evans, 2009; Evans et al., 2010]. Approximately half of cases occur sporadically as a result of new mutation. The NF2 gene was mapped to chromosome 22 [Rouleau et al., 1987], and the responsible gene was identified by two groups in 1993 [Rouleau et al., 1993; Trofatter et al., 1993]. The protein is variously referred to as schwannomin or merlin (the latter an acronym for moesin, ezrin, and radixin-like protein]. Merlin is a cytoskeletal protein that appears to play a role in the control of cell growth in tissues [Xiao, Chernoff and Testa, 2003]. Schwannomas are clonal tumors, and the NF2 gene acts as a tumor suppressor in formation of these tumors, as well as other NF2-associated tumors [Seizinger et al., 1987]. Genetic testing for NF2 is available for diagnostic purposes. Some genotype–phenotype correlations have been identified; specifically, missense or splicing mutations tend to predict milder disease than do mutations that lead to protein truncation [Parry et al., 1996; Ruttledge et al., 1996]. Somatic mosaicism for NF2 mutation may produce localized disease or ameliorate disease severity [Baser et al., 2000a].

Management

Patients benefit from multidisciplinary care at a center with experience in dealing with the varied manifestations of the disorder [Evans et al., 1993]. Management of tumors associated with NF2 is primarily surgical [Evans et al., 2005]. Timing of surgery and the decision to treat one or both vestibular tumors depends on tumor size, degree of hearing loss, and involvement of other cranial nerves or compression of the brainstem. Stereotactic radiosurgery is also used for the treatment of vestibular schwannomas [Battista, 2009], though there may be an increased risk of malignancy in residual tumor [Baser et al., 2000b]. Recent trials with the vascular endothelial growth factor (VEGF) inhibitor bevacizumab have shown promising results in reduction in size of vestibular schwannomas [Plotkin et al., 2009; Mautner et al., 2010].