Chapter 141. The Neurofibromatoses

The “modern age” of neurofibromatosis began in 1981, with Riccardi's detailed clinical descriptions of the features and natural history of von Recklinghausen disease and the subsequent description of “central neurofibromatosis with bilateral acoustic neuroma.” With the availability of gene-based diagnosis, several distinct clinical syndromes have been identified: (1) neurofibromatosis type 1 (NF-1), also known as von Recklinghausen disease; (2) neurofibromatosis type 2 (NF-2), whose cardinal feature is the development of bilateral vestibular schwannomas; (3) segmental or mosaic NF-1; (4) Legius syndrome (SPRED1 mutation) leading to autosomal dominant transmission of café-au-lait spots, intertriginous freckling and macrocephaly; and (5) schwannomatosis. Both NF-1 and NF-2 occur equally in all ethnic groups. NF-1 occurs at an incidence of 1 in 3,000 live births, whereas NF-2 is much less common with an estimated incidence of 1 in 40,000 live births.

Genetics

NF-1 is inherited in an autosomal dominant fashion. Although the expressivity of NF-1 varies considerably, even among individuals in the same family who are genotypically identical, the disorder is considered to be 100% penetrant. Thus, apparent skipping of NF-1 between generations may be the result of misdiagnosis, nonpaternity, or the occurrence of a new mutation in the grandchild. Although a large number of NF1 mutations have been described, only two genotype-phenotype correlations have been noted. Individuals who have deletions of the entire NF1 gene have an increased risk of facial dysmorphism, mental retardation, early appearance of neurofibromas, and the presence of plexiform neurofibromas.1 In addition, individuals who have a specific 3 base pair in-frame deletion in exon 17 of the NF1 gene may have café-au-lait spots, intertriginous freckling and Lisch nodules, but do not develop cutaneous, subcutaneous or plexiform neurofibromas. neurofibromas. There is evidence that NF-1 is more severe when inherited from the mother rather than from the father.

The gene NF1 is located on the long arm of chromosome 17, and encodes a protein called neurofibromin. Homozygosity for mutant NF1 alleles has not been reported, probably because it is a lethal condition. NF1 has an unusually high mutation rate, estimated at 2.4 × 10−5 to 10 × 10−5 gametes per generation, one of the highest of known inherited disorders.2 This may reflect the large size of the gene, which spans 350 kb of genomic DNA, and contains 59 exons which encode a peptide containing over 2,800 amino acids. An alternative hypothesis is that there is some structural property of the gene that renders it particularly susceptible to mutation. New mutations account for approximately 50% of cases, and are usually on the paternally inherited allele. In contrast to many other dominant disorders, the frequency of new mutations does not appear to increase with advancing paternal age.

Molecular Biology

Most NF1 mutations result in reduced intracellular levels of the NF1 gene product, neurofibromin; this appears to be sufficient to cause many of the clinical manifestations of the disease. Tumorigenesis, including the development of benign dermal neurofibromas, appears to be dependent on inactivation of the normal NF1 allele in somatic cells, a process referred to as loss of heterozygosity.3 Loss of heterozygosity is a critical step in tumorigenesis in many inherited cancer predisposition syndromes (e.g., retinoblastoma, Li-Fraumeni syndrome), and the genes involved are called “tumor suppressor genes.” Tumorigenesis is initiated when both copies of the gene cease functioning normally—the first as a result of an inherited mutation, and the second as the result of a second somatic “hit” interfering with the function of the previously normal allele.

Neurofibromin is found in a variety of cell types, including neurons, oligodendrocytes, and nonmyelinating Schwann cells. Considerable evidence has been developed for the role of neurofibromin as a negative regulator of RAS.4,5 The RAS gene family encodes membrane-associated, guanine nucleotide-binding proteins that are involved in the regulation of cellular proliferation, differentiation, and learning. RAS exists in an active (RAS-GTP) and inactive (RAS-GDP) state. By favoring conversion of RAS from its active state to its inactive state, neurofibromin downregulates the downstream effects of RAS, which include promoting learning, memory, synaptic plasticity, and cell growth and proliferation.4,6 Mediators of the downstream effects of RAS include mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), protein kinase B (PKB), and mammalian target of rapamycin (mTOR) kinase. Spred1 also inhibits activation of the MAPK pathway.

Four different forms of neurofibromin exist, resulting from alternate splicing. The type II variant includes a 21 amino acid sequence encoded by exon 23a, while type I does not. This sequence appears to be critical for RAS regulation and learning. In the brain, there are three major isoforms of RAS; K-RAS has been shown to be the primary target of neurofibromin activity.5 Activation of RAS by neurofibromin stimulates G-protein activity, resulting in activation of adenylyl cyclase. Cyclic AMP and other downstream intermediates appear to play a role in cell growth, learning, and memory. Neurofibromin also associates with microtubules and plays a role in regulating GABA-ergic inhibitory neuronal activity in the hippocampus.7

RAS is a membrane-bound protein, and requires farnesylation (addition of a C15 isoprenoid to a cysteine residue near the C-terminus) for activity, a process that is catalyzed by farnesyltransferase. Agents that inhibit farnesyltransferase cause general inhibition of the RAS pathway, much as neurofibromin does. Farnesyltransferase inhibitors reverse the proliferative phenotype in Nf1-deficient mouse cells, and can reverse spatial learning impairments in a mouse model of NF1, by decreasing RAS levels.6 These observations have prompted investigations into the use of farnesyltransferase inhibitors for the treatment of NF-1-related complications, such as rapidly growing plexiform neurofibromas.

Loss of heterozygosity of the NF1 gene in Schwann cells has been shown to be the necessary event for the development of discrete neurofibromas.8 Furthermore, neurofibromin-deficient Schwann cells secrete a substance which stimulates mast cell migration which, in turn, stimulates production of extracellular matrix and angiogenesis.9 Astrocytes lacking NF1 expression cannot form optic nerve gliomas on their own; a brain environment heterozygous for NF1 is necessary for the development of these tumors.10

A consensus development conference was held by the National Institutes of Health in 1987 in order to establish diagnostic criteria to promote better clinical research and care of patients with NF-1.11 The seven diagnostic features recognized at this conference (Table 141-1), and the recommendation that two or more of these seven features be present before a diagnosis of NF-1 is established, have proven extremely useful and continue to be used without modification 20 years later. Perhaps the one caveat is the identification of a separate autosomal dominant syndrome caused by an inactivating mutation of the gene encoding sprouty-related EVH1 domain-containing protein 1 (SPRED1) which leads to the development of café-au-lait spots, intertriginous freckling, and macrocephaly, but none of the other manifestations of NF-1 (Legius syndrome).12

Café-Au-Lait Spots

Café-au-lait spots, which are flat, pigmented macules, are often the first manifestation of NF-1 to appear (Fig. 141-1). Frequently present at birth, they become more numerous as the infant grows; new ones may continue to appear throughout the first decade of life. Once noticed, they tend to grow in size in proportion to the overall growth of the child. Although infrequently found on the face, they may be noted anywhere on the body. The size, shape and contour of café-au-lait spots are of no diagnostic significance, and the oft-quoted adage about smooth-edged café-au-lait spots being more typical of NF-1 rather than McCune–Albright syndrome is incorrect (see Section “Differential Diagnosis” and Box 141-1). When café-au-lait spots overlap each other, the area of overlap may be darker than either individual spot. When found within Mongolian spots, they are typically surrounded by a more lightly pigmented halo. Individuals with large numbers of café-au-lait spots do not have “more severe” NF-1, and the location of the macules in no way predicts the location of subsequent neurofibromas.13

Café-au-lait spots represent collections of heavily pigmented melanocytes of neural crest origin in the epidermis. Although the cells may contain increased numbers of “giant” melanosomes, or melanin macroglobules, these are not unique to NF-1, and their presence or absence in biopsies is not helpful diagnostically.

The diagnostic criterion for NF-1 is six or more café-au-lait spots greater than 5 mm in diameter in prepubertal individuals or 1.5 cm in adults. Of all children ultimately diagnosed with NF-1, 53% will have six or more café-au-lait spots by age 3 years and 97% by age 6 years.14

Intertriginous Freckling

Café-au-lait spots smaller than 5 mm are referred to as freckles, and are commonly present in the axillae, inguinal region, and under the breasts (Fig. 141-2). Unlike ordinary freckles in these locations, these lesions are not related to sun exposure, and are considered virtually pathognomonic of NF-1 (Crowe's sign). Of all children ultimately diagnosed with NF-1, 81% will have intertriginous freckling by age 6 years.14

Discrete Neurofibromas

Neurofibromas, which consist of Schwann cells, mast cells, fibroblasts, and perineural cells, are benign nerve sheath tumors that appear as discrete masses arising from peripheral nerves.15 Cutaneous neurofibromas protrude just above the skin surface or lie just under the skin with an overlying violaceous hue (Fig. 141-3). They are softer than the surrounding connective tissue, often creating a “buttonholing” sensation when a finger is rubbed gently over the surface (Fig. 141-4). Subcutaneous neurofibromas that arise from peripheral nerves, both under the skin and deep in the viscera, are generally much harder (Fig. 141-5). If they arise from the dorsal root ganglia, they may grow through neural foramina, compressing the spinal cord, creating a “dumbbell” appearance. Subcutaneous neurofibromas in the neck may feel like a “beaded necklace,” often being confused with lymph nodes. While less than 20% of children under 10 years of age have cutaneous neurofibromas,14 they generally start appearing after puberty and increase in number as the patient grows older. Women who have NF-1 often comment on the appearance of cutaneous neurofibromas during pregnancy. The majority of adult patients with NF-1 probably have numerous asymptomatic deep neurofibromas involving the dorsal roots and other larger nerves. On occasion, neurofibroma-associated pruritus may be severe enough to require treatment with antihistamines.

Plexiform Neurofibromas

Plexiform neurofibromas, histologically similar to discrete neurofibromas, are benign peripheral nerve sheath tumors which involve single or multiple nerve fascicles, often arising from branches of major nerves.16 They may elicit a “wormy” sensation on palpation, as one feels multiple thickened nerve fascicles. Often there is overlying hyperpigmentation (“giant café-au-lait spot”) or hypertrichosis (Fig. 141-6). Most plexiform neurofibromas are present at birth or become apparent during the first several years of life. Externally visible plexiform neurofibromas are easily identified and may lead to disfigurement, blindness (secondary to amblyopia, glaucoma, or proptosis), or loss of limb function (eFig. 141-6.1, Fig. 141-7, Fig. 141-8). In contrast, thoracic or abdominal plexiform neurofibromas may have no external manifestations but may have equally devastating consequences due to invasion or compression of vital structures (e.g., ureters, bowel, spinal cord, etc.).

The growth rate of plexiform neurofibromas is highly variable. Periods of rapid growth alternating with long periods of quiescence are common. Malignant peripheral nerve sheath tumors, which generally arise from plexiform neurofibromas, may develop silently in deep plexiform neurofibromas and not give rise to symptoms until distant metastases have occurred. While loss of heterozygosity at the NF-1 locus may lead to the formation of benign neurofibromas, the generation of malignant transformation of a benign plexiform neurofibroma may be due to cell cycle regulators beyond the ras oncogene. For example, mice which have null mutations in both the Nf-1 and p53 genes uniformly develop malignant tumors.17,18 Physicians caring for individuals with NF-1 should be alert to development of a malignancy; plexiform neurofibromas should be biopsied if they exhibit rapid growth or cause significant pain or focal neurologic dysfunction.

Optic Pathway Tumors

Approximately 15% of children with NF-1 will develop optic pathway tumors (OPT); however, only half of these patients will ever develop symptoms, giving an overall incidence of symptomatic OPT of 7%.19,20 Recent series of NF-1-associated OPT have identified an approximately 2:1 female predominance of patients, as well as a lower incidence in African-American children. These observations suggest the possibility that either hormonal factors or modifying genes may influence the development of OPT.

The period of greatest risk for the development of symptomatic OPT in NF-1 is during the first 6 years of life. In addition, the development of a symptomatic tumor after age 6 years is extremely unusual.19,20 Thus, physicians caring for children with NF-1 should be sensitive to the signs and symptoms of OPT in this young age group. Approximately 30% of children with symptomatic OPT will present with the rapid onset of proptosis, with moderate to severe visual loss in the affected eye (eFig. 141-8.1). Another 30% of children will have abnormal ophthalmologic examinations, without any visual symptoms, leading to discovery of the tumors. As young children rarely complain of visual loss, even when severe, thorough annual eye examinations are imperative in all young children with NF-1. When present, ophthalmologic signs may include an afferent papillary defect, optic nerve atrophy, papilledema, strabismus, or defects in color vision. Finally, as many as 40% of children who have chiasmal tumors develop precocious puberty. Accelerated linear growth will be the first sign of precocious puberty, underscoring the need for all children with NF-1 to have annual assessments of growth using standard growth charts. Children with chiasmal tumors often have no ophthalmologic symptoms or signs. Early detection of precocious puberty is important as both the accelerated linear growth and the development of secondary sexual characteristics can be can be aborted with the use of a long-acting luteinizing hormone releasing hormone agonist.21

Lisch Nodules

Lisch nodules are slightly raised, well-circumscribed melanocytic hamartomas of the iris thought to be virtually pathognomonic of NF-1 (Fig. 141-9). They are best seen using a slit lamp, which is necessary to distinguish them from the more commonly seen flat iris nevi, which are not associated with NF-1. They do not cause any functional impairment of vision. The frequency with which they are found increases with age; although Lisch nodules are found in over 90% of adults with NF-1, only 30% of children with NF-1 under 6 years of age have them.14

Distinctive Osseous Lesions

There are two bony lesions distinctive enough to be included in the diagnostic criteria for NF-1. The first, dysplasia of the wing of the sphenoid bone, results in poor formation of the wall and/or floor of the orbit (eFig. 141-9.1). This congenital mesodermal dysplasia may be, but is not always, clinically apparent leading to proptosis (from herniation of meninges or brain into the orbit) or enophthalmos.

Dysplasia of a long bone, characterized by congenital thinning and bowing, affects approximately 2% of children with NF-1 (eFig. 141-9.2). Although the tibia is most commonly affected, the femur, humerus and other long bones may also be involved. Even when the bone is intact, thinning and bowing produce a visible deformity, and the weakened mechanical properties of the bone predispose to fracture, particularly in the weight bearing bones. Failure of primary union following a fracture results in a “false joint,” or pseudarthrosis.22

Laboratory Tests

Despite the identification of the NF-1 gene and its complete sequencing, the diagnosis of NF-1 remains primarily a clinical one. Although laboratory confirmation of the diagnosis is extremely useful in specific circumstances, in most cases it is unnecessary. Since no common mutations have been identified, molecular diagnosis can only be based on strategies that screen the entire gene for mutations. Several laboratories now offer sequencing of some or all exons and/or mutation scanning with a resulting sensitivity of as high as 95%. This testing is available for both presymptomatic individuals and can be applied to prenatal diagnosis of NF-1 when a mutation has been identified in an affected parent.

Inexperienced clinicians often biopsy cutaneous masses in an effort to confirm the diagnosis of NF-1 in an individual with multiple café-au-lait spots or other stigmata of NF-1. Such procedures are invariably unnecessary as the clinical diagnosis of NF-1 is usually quite straightforward. Biopsy of a plexiform neurofibroma should be reserved for those situations in which the physician wishes to exclude the possibility of a malignancy.

Radiographic Evaluation

There has been considerable debate regarding the role of screening neuroimaging in the care of asymptomatic children with NF-1. Routine “screening” would be important if it led to early detection of OPT and early initiation of therapy which prevented visual deterioration. A longitudinal study of children with NF-1 failed to identify any tumors in which early detection altered the patient's clinical course.19 Moreover, targeted screening of very young children with NF-1, the high-risk group for the development of OPT, failed as three children developed symptomatic tumors shortly after having had normal MRI scans. Brainstem tumors in both children and adults with NF-1 are generally more indolent than their counterparts in non-NF-1 individuals, suggesting that routine screening would not be beneficial.23 Thus, the National Neurofibromatosis Foundation Optic Pathway Task Force has recommended against routine screening neuroimaging of all children with NF-1.24). Although there are no comparable longitudinal data for adults regarding the performance of “routine” MRI scans of the head and spinal cord, it seems reasonable to perform such testing only in individuals who have symptoms or signs suggestive of CNS pathology.

Similarly, there is debate as to whether patients with NF-1 should be “screened” for the presence of hidden, internal plexiform neurofibromas; most studies have demonstrated an approximately 30% incidence.25,26 Newer techniques utilizing whole body MRI scans have been shown to reliably assess the entire tumor burden of individuals with NF-1.27 As such a strategy incurs great cost without offering any proven benefit in preventing morbidity from plexiform neurofibromas, it is not recommended.28 However, if current chemotherapeutic trials prove successful in the treatment of rapidly growing tumors, their identification at an early age may become more important.

Skeletal Complications

All children with NF-1 should be regularly screened for scoliosis, beginning in early childhood. Scoliosis is the most common skeletal manifestation of NF-1, affecting 10%–30% of patients. Scoliosis is divided into dystrophic and nondystrophic types. Dystrophic scoliosis is the result of primary bone dysplasia, and may present very early in childhood, typically resulting in a sharply angulated curve spanning relatively few vertebral bodies (eFig. 141-9.3). It is often accompanied by extreme rotation, scalloping of the posterior margins of the vertebral bodies, vertebral wedging, defective pedicles, and enlargement of the neural foramina and spinal canal.22 The curvature may progress rapidly, necessitating surgery which may be particularly complicated because of the complex, multiplanar curves, poor quality of bone, potential for nerve root and spinal cord injury, and the presence of intraspinal and extraspinal neurofibromas. The nondystrophic type of scoliosis is more common, and is similar to idiopathic scoliosis in adolescents. Many children can be managed expectantly or with bracing.

Localized regions of bony overgrowth may also occur in children with NF-1 and are often in areas free of neurofibromas. The overgrowth may affect only a single digit or a larger region such as a hand or an extremity, but true hemihypertrophy is unusual. Bony overgrowth may also occur in a region affected by a plexiform neurofibroma.

Cancer

There is little doubt that NF-1 predisposes one to an increased risk for certain cancers. In a Swedish cohort of 212 probands and their affected relatives followed for more than 40 years, malignant neoplasms or central nervous system tumors occurred in 45% of the probands, for a relative risk of 4 compared with that in the general population. However, when the affected relatives of the probands were examined, only the female relatives with NF-1 had an increased risk of neoplasms.29 This illustrates the tremendous bias inherent in data obtained through hospital records and disease-specific clinics. In reviewing the records of Japan's Children's Cancer Registry, the incidence of NF-1 was 6.45 times the expected estimated rate.30

Malignant peripheral nerve sheath tumors almost exclusively arise from preexisting plexiform neurofibromas. Estimates of the lifetime risk for the development of this tumor vary but may be as high as 13%.31,32 As the outcome of therapy is poor, physicians should be diligently aware of the early symptoms referable to these tumors including a rapidly growing mass or unexplained pain or dysfunction. Although conventional imaging cannot identify malignant tissue within a benign plexiform neurofibroma, newer modalities such as 18-fluorodeoxyglucose positron emission tomography may be useful.33

Pheochromocytoma clearly is associated with NF-1 with an incidence potentially as high as 1.4%. In a recent review, the mean age at presentation was 42 years; 84% had solitary adrenal tumors, 9.6% had bilateral adrenal tumors, and 6% had ectopic tumors in the abdominal sympathetic chain, organ of Zuckerkandl, and the bladder.34 Catecholamine-associated symptoms and hypertension each were present in 61% of the patients; 22% of the patients had neither of these findings. Malignant pheochromocytomas were found in 11.5% of patients, often with distant metastases at presentation. Loss of heterozygosity of the NF-1 gene has been demonstrated both in NF-1-associated and sporadic pheochromocytomas.35,36

There is an increased risk of chronic myelomonocytic leukemia and acute lymphoblastic leukemia in children with NF-1. In contrast to the fourfold predominance of lymphocytic leukemia generally seen in childhood, there is a clear excess of cases of myelogenous leukemia in children with NF-1.37 Homozygous inactivation of the NF-1 gene in the bone marrow cells children with NF-1 and malignant myeloid disorders have been identified, suggesting that the NF-1 gene plays a role in downregulating the growth of immature myeloid cells.38 Some children with NF-1 also develop juvenile xanthogranulomas, yellowish papules less than 1 cm in diameter that are usually found on the head or trunk (Fig. 141-10) and may be multiple.

An unusual association between juvenile xanthogranulomas, NF-1, and the development of myeloid leukemias has been reported.39,40 Although the pathogenesis is obscure, this association also has been observed independent of NF-1. Juvenile xanthogranulomas are yellowish papules less than 1 cm in diameter usually found on the head or trunk. Some authors have recommended “screening” blood counts for individuals who have juvenile xanthogranulomas and NF-1. Given that the magnitude of the risk is unknown but certainly extremely small, this recommendation only serves to increase parental anxiety without providing any useful information and is not endorsed by the authors. Rhabdomyosarcoma also occurs more frequently in individuals with NF-1.41,42 Although a relationship between both neuroblastoma and Wilms tumor and NF-1 has been suggested, there are no strong epidemiologic data linking these tumors with NF-1. Other tumors that appear to occur in excess frequency in adults with NF-1 are somatostatinomas of the duodenum and the ampulla of Vater, and gastrointestinal stromal tumors (GIST). Compared to those tumors seen in non-NF-1 individuals, somatostatinomas in NF-1 rarely arise in the pancreas, are smaller, and generally are not associated with hormonal symptoms (i.e., diabetes, steatorrhea, and gallbladder disease).43

Vasculopathy

Patients with NF-1 may have a vasculopathy affecting essentially any arterial vessel. Clinical manifestations may include renal artery stenosis with hypertension, cerebral infarcts, bleeding aneurysms, and intermittent claudication of an extremity. This vasculopathy is a developmental problem not related to compression of an arteriole by a neurofibroma, and appears to be acquired after birth, as the appearance of new lesions and the progression of preexisting ones have been described. Characteristic pathologic changes have been described in all layers of the vascular wall which ultimately leads to narrowing of the arterial lumen.44,45

The most commonly identified vascular lesion in patients with NF-1 is in the renal artery, leading to renovascular hypertension.46 Renal artery vasculopathy should be considered in any adult NF-1 patient with hypertension that is not easily controlled with a single antihypertensive medication; all NF-1 children should be evaluated for this complication. Aortography with selective angiography of the renal arteries should be used to confirm the diagnosis. If the blood pressure is uncontrollable using oral antihypertensives, percutaneous transluminal angioplasty can be performed and repeated if initially unsuccessful.

Unidentified Bright Objects

Brain magnetic resonance imaging of children with NF-1 frequently demonstrates regions of increased signal intensity on T2-weighted images, referred to as “unidentified bright objects” or UBOs (eFig. 141-10.1). UBOs may be found in the internal capsule, basal ganglia, cortex, cerebellar hemispheres, optic tract, or brainstem. They do not enhance and are not associated with compression of surrounding tissue, which distinguish them from neoplasms. UBOs are present in approximately 60% of children with NF-1, but disappear with age, and are uncommon in adults. They are not associated with focal neurologic signs, and are of uncertain significance. Histopathologic studies have shown that the UBOs corresponded to areas of myelin vacuolization with increased water content.47 Recent studies have found that NF-1 children with UBOs have significantly lower IQ and language scores, significantly impaired visual-motor integration and motor coordination, and are at much greater risk for impaired academic achievement, when compared with NF-1 subjects without UBOs.48

Intelligence and Learning Disabilities

Contrary to gross misstatements in the older literature, the mean IQ of patients with NF-1 is only 5–10 points lower than the general population and unaffected siblings.49 However, learning disabilities, defined as discrepancies between ability (intellect) and performance, are quite common with an estimated prevalence of 30%–60%.50,51 Although earlier reports suggested there might be a specific “cognitive phenotype” in NF-1 characterized by an excess of visual/perceptual disabilities, more recent studies have demonstrated that verbal deficits (e.g., reading) are at least as common as nonverbal disabilities in individuals with NF-1. These learning disabilities are lifelong and can affect adult functioning. Many children with NF-1 also have poor attention and impulse control, and may be diagnosed with attention deficit hyperactivity disorder, significantly interfering with school performance and learning. Stimulant medications may have a profound beneficial effect on these individuals’ ability to succeed academically and professionally.

Individuals with NF-1 are best cared for within a multidisciplinary clinic, which has access to a wide range of subspecialists. The exact physician composition of the clinic is less important than the ability to obtain expeditious subspecialty consultation. All first-degree relatives should be examined for the cutaneous manifestations of NF-1 and should undergo slit-lamp examination at the first visit to ascertain the presence of Lisch nodules. Yearly visits allow the physician to identify NF-1 complications early while providing counseling and dissemination of information regarding NF-1.13 Individuals and families can obtain further information from the Web sites of the two national support groups: (1) the Children's Tumor Foundation (www.ctf.org) and (2) Neurofibromatosis, Inc. (www.nfinc.org).

All children with NF-1 who are 6-years-old and younger should have yearly complete ophthalmologic examinations looking for signs of an optic pathway tumor. These should include assessment of visual acuity, color vision, visual fields, fundoscopy, and slit-lamp examination. As almost all optic pathway tumors arise in children in this age group, the frequency of ophthalmologic examinations can be reduced in children over 10 years of age. Yearly measurements of weight and height should be plotted on standardized growth charts, as the earliest indication of precocious puberty may be accelerated linear growth. Blood pressure measurements should be obtained at each visit to look for signs of renovascular hypertension. In addition, the spine should be examined each year for early signs of scoliosis.13

Café-Au-Lait Spots

Café-au-lait spots on the face are unusual in individuals with NF-1. On occasion, they do occur and affected individuals may seek to improve cosmesis. Attempts at removing café-au-lait spots with laser therapy have provided very mixed results. Although total disappearance of the lesion may occur, some studies cite a recurrence rate as high as 67%. While results with use of the Q-switched ruby laser (694 nm) have been mixed, favorable reports in a limited number of cases using either the continuous mode copper vapor laser (511 nm) or the erbium:YAG laser (2,940 nm) have been published.52,53 Multiple treatments of a single lesion may be more effective.

Cutaneous Neurofibromas

Discrete cutaneous neurofibromas may be removed surgically to improve cosmesis or to prevent local irritation, for example, in the hairline while brushing or on the foot rubbing against the shoe. Deeper neurofibromas may require surgical removal when pushing on vital structures, such as a dorsal root neurofibroma that infiltrates the neural foramen and compresses the spinal cord. Complications of surgery include regrowth of the original tumor and nerve damage. In individuals who have severe pruritus from a large burden of cutaneous neurofibromas, antihistamines may provide symptomatic relief. Uncontrolled anecdotal case reports have suggested that ketotifen, an antihistamine and mast cell stabilizer, has provided relief from pruritus and pain and prevented the rapid growth of new neurofibromas.54 Use of the CO2 laser under general anesthesia to remove hundreds of cutaneous neurofibromas has resulted in markedly increased patients’ quality of life and decreased pain and pruritus.55 The residua of a flat smooth depigmented scar was not felt to be an impediment to such surgery by most patients.

Plexiform Neurofibromas

Until recently, the treatment of plexiform neurofibromas was limited to surgical debulking either to improve cosmesis or to prevent loss of function (e.g., upper airway obstruction, blindness). Such surgery was highly limited in its efficacy; complete resection was impossible given the highly infiltrative nature of these tumors and tumor regrowth was common. Thus, there has been considerable interest in the development of nontraditional chemotherapy for use against these tumors. Not surprisingly, the design of studies to test the efficacy of such agents is fraught with complications. Plexiform neurofibromas are quite different biologically from more conventional solid neoplasms. Lack of growth following treatment may be part of the natural history of the tumor rather than a true therapeutic response. In addition, tumor burden may be difficult to quantify radiographically; plexiform neurofibromas may “spread” along nerve roots sending out multiple finger-like projections, quite different than a single, solid tumor mass.

Despite the above difficulties, several Phase I and II chemotherapeutic trials are in progress. Preliminary studies utilizing pirfenidone, an antifibrotic agent that decreases proliferation of fibroblasts and collagen matrix synthesis, and a farnesyltransferase inhibitor which downregulates the ras oncogene, did not yield promising results. In a recently described case and based on studies of the important role of mast cell c-kit receptor signaling, administration of imatinib to a 3-year-old with an unresectable airway plexiform neurofibroma led to 70% diminution in size during 3 months of therapy.56 Other newer agents are also currently being studied. These include: (1) AZD2171, which is a potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases; (2) sirolimus, an mTOR pathway inhibitor; (3) PEG interferon-α-2b; and (4) photodynamic therapy. If any of these studies demonstrate potential efficacy, the role of screening imaging to detect “hidden” plexiform neurofibromas would need to be readdressed.

Optic Pathway Tumors

Once identified, OPT should be followed by serial MRI and ophthalmologic examinations. Treatment should be initiated only after demonstration of clear radiographic progression or deterioration of vision. The goal of treatment should be preservation of vision while minimizing the side effects of therapy. Chemotherapy with carboplatin and vincristine has proven effective in the management of these tumors.57 Radiation therapy, while a mainstay of treatment of progressive CNS neoplasms not associated with NF-1, is not appropriate for NF1-associated OPTs because of the risk of vasculopathy, second malignancies, and detrimental neurocognitive and endocrinologic side effects in very young children.

Neurofibromatosis-2 (NF-2)

NF-2 is an autosomal dominantly inherited condition characterized by bilateral vestibular schwannomas, meningiomas (intracranial, intraspinal, and optic nerve sheath), schwannomas (dorsal roots of the spinal cord, peripheral nerves, and cranial nerves), ependymomas and gliomas of the central nervous system, and juvenile posterior subcapsular cataracts.58 The estimated birth incidence is 1 in 40,000 live births. While much less common than NF-1, its morbidity is much greater, with patients frequently becoming paralyzed and deaf. The most recent clinical diagnostic criteria have led to increased sensitivity in establishing the diagnosis, particularly in those cases without a positive family history (Table 141-2). Approximately 60% of patients present in adulthood with hearing loss, tinnitus, or loss of balance. The younger the age at presentation, the greater the ultimate severity of the disease. Children are more apt to present with a noneighth nerve tumor such as an optic nerve sheath meningioma. Ophthalmologic findings include juvenile posterior subcapsular cataracts (60%–80% of patients), retinal hamartomas, and optic nerve sheath meningiomas.58

Individuals with NF-2 may have several café-au-lait spots, but rarely have more than six; intertriginous freckling is not seen. The characteristic cutaneous lesion of NF-2 is the cutaneous schwannoma (Fig. 141-11). It is a plaque-like, slightly raised lesion with a faint violaceous hue, occasionally with hair. Less commonly, cutaneous neurofibromas, indistinguishable from those seen in NF-1, may be found.

NF-2 is caused by mutations in a gene on chromosome 22, which encodes the membrane-related protein merlin, also known as schwannomin. As in NF-1, the NF-2 gene is a tumor suppressor gene which downregulates cellular growth. The exact cellular pathways by which this control is exerted have yet to be delineated.

Segmental NF-1

The term “segmental neurofibromatosis” refers to individuals who have manifestations of NF-1, usually café-au-lait macules and neurofibromas, limited to one area of the body.59 Ruggieri and Huson have proposed use of the term “mosaic localized NF-1” for these individuals, as an acknowledgement that the pathogenesis of this condition is a postconceptional mutation in the NF-1 gene leading to somatic mosaicism.60 This has been confirmed in a patient in whom the mutant NF-1 allele was present in a mosaic pattern in cultured fibroblasts from a café-au-lait macule and absent in fibroblasts from normal skin.61

The vast majority of patients with segmental NF-1 have café-au-lait macules or intertriginous freckling limited to one area of the body (Fig. 141-12). These individuals are at risk for developing complications of NF-1 in the affected area, most commonly neurofibromas. Localized manifestations of NF-1 other than café-au-lait macules, freckling, or cutaneous neurofibromas may also represent examples of somatic mosaicism. There have been numerous reports of isolated plexiform neurofibromas, including one case in which loss of heterozygosity of the NF-1 gene in Schwann cells from the tumor was demonstrated. Since only 50% of cases of tibial pseudarthrosis occur in the context of NF-1, the others may actually represent cases of segmental NF-1. Other examples of segmental NF-1 include a child who had a unilateral optic pathway glioma that acted that acted biologically like an NF-1-associated tumor and individuals with isolated sphenoid bone dysplasia.

Genetic counseling of patients with segmental NF-1 is problematic. Many of these patients are misdiagnosed as having NF-1, leading to unnecessary anxiety and inappropriate genetic counseling. In addition, gonadal mosaicism for NF-1 has been demonstrated; patients with segmental NF-1 have had offspring with complete NF-1.

NF1–Noonan Syndrome

It has been recognized that there are individuals who meet the diagnostic criteria for NF-1, yet have many features of Noonan syndrome, which is characterized by hypertelorism, ptosis, downsloping palpebral fissures, low set, posteriorly rotated ears, webbed neck, pectus deformities, and short stature. Over 50% of children with Noonan syndrome have cardiovascular disease, most commonly pulmonary valve stenosis. Noonan's syndrome is caused by mutations in the gene PTPN11 in 50% of cases. Mutations in several other genes (KRAS, SOS1, BRAF, MEK1, MEK2, HRAS and RAF1) have also been associated with this phenotype. Genetic testing has shown that most individuals with LEOPARD syndrome also have mutations in PTPN11. A recent study documented mutations in the NF-1 gene in 16 of 17 unrelated subjects who clinically had the NF-1–Noonan phenotype; no mutations in PTPN11 were found.62 Thus, it appears that the vast majority of cases of NF-1–Noonan syndrome are due to mutations in NF-1.

Legius Syndrome

Families recently have been identified who have autosomal dominant transmission of café-au-lait spots, intertriginous freckling, and macrocephaly without any other manifestations of NF-1, including neurofibromas, in whom no NF-1 mutation was detected. Further genetic studies of these individuals revealed mutations in SPRED1, a gene that negatively regulates the mitogen-activated protein kinase (MAPK) pathway. None of these individuals has discrete neurofibromas, plexiform neurofibromas, Lisch nodules, optic pathway tumors, or NF-1-specific bony abnormalities.12 The frequency of cognitive deficits in these individuals is, as yet, unknown. Genetic testing for SPRED1 mutations is available in individuals suspected of having Legius syndrome in whom NF-1 gene testing has failed to detect a mutation.

Schwannomatosis

It had been noted for some time that there are patients who develop multiple schwannomas but who fail to develop other manifestations of NF-2, particularly vestibular schwannomas.63,64 Patients with this condition, now called schwannomatosis, develop multiple painful schwannomas within peripheral nerves and paraspinal nerve roots. The tumors most often start appearing during the second and third decades of life. Surgery of individual lesions is often necessary to treat intractable pain. In contrast to NF-2, individuals with schwannomatosis have a normal life span. Before making a diagnosis of schwannomatosis, it is extremely important to exclude the possibility of NF-2 by both genetic testing and performing an MRI scan to look for vestibular schwannomas. Germ-line mutations in SMARCB1/INI1, another tumor-suppressor gene previously implicated in the development of rhabdoid tumors in infants and young children, have been identified as the cause of a large number of the familial cases of schwannomatosis.65