Introduction. Overview

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1 Neurofibromatosis type 1 Wendy Sherman MD (Dr. Sherman of Feinberg School of Medicine at Northwestern University in Chicago, Illinois, has no relevant financial relationships to disclose.) Jeffrey J Raizer MD (Dr. Raizer, Medical Director of Neuro-Oncology at Feinberg School of Medicine at Northwestern University, received honorariums from Agenus, BMS, Genentech, Novartis, and Stemline for service on advisory boards; honorariums from Genetech and Merck for speaking engagements; and stock options from Aurasense for service on their advisory board.) Edward J Dropcho MD, editor. (Dr. Dropcho of Indiana University Medical Center has no relevant financial relationships to disclose.) Originally released March 21, 1995; last updated August 4, 2014; expires August 4, 2017 Notice: This article has expired and is therefore not available for CME credit. Introduction This article includes discussion of neurofibromatosis type 1, NF1, peripheral neurofibromatosis, and Von Recklinghausen neurofibromatosis. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations. Overview Neurofibromatosis 1 is an autosomal dominant neurocutaneous disorder displaying a stereotyped pattern of dermatologic and systemic findings. It was first described in 1882 by von Recklinghausen in Germany and later differentiated from neurofibromatosis type 2. In the past decade, with advancements in molecular genetics studies, research has led to further understanding of the genotype and consequence phenotype of neurofibromatosis type 1. In this article, the authors address the recent advancements in neurofibromatosis type 1 studies. Key points Neurofibromatosis type 1 is an autosomal dominant genetic disorder characterized by the prominent cutaneous manifestations of café au lait spots, skin-fold freckles and neurofibromas, hamartomatous nodules of the iris, dysplasia of bones, and a tendency to develop certain types of tumors, especially of the peripheral and central nervous system. The gene locus for neurofibromatosis type 1 is found on chromosome 17, which is thought to lead to loss of transcription of neurofibromin, resulting in the disease manifestations of neurofibromatosis type 1. There is currently no specific preventative treatment for any of the disease features of neurofibromatosis type 1; though the consequences of some disease complications may be prevented, or at least minimized, by timely interventions. Legius syndrome is a neurofibromatosis type 1-like syndrome characterized by café au lait macules, axillary freckling, and macrocephaly but is not associated with peripheral and nervous system tumors, as in neurofibromatosis type 1. Historical note and terminology Neurofibromatosis is a term applied to a spectrum of disorders with some overlapping clinical features. The 2 best of these that are best characterized are neurofibromatosis type 1, formerly known as von Recklinghausen disease or peripheral neurofibromatosis, and neurofibromatosis type 2, also known as bilateral acoustic or central neurofibromatosis, each with distinctive clinical features and genetic origins on different chromosomes (Korf 1990). Neurofibromatosis type 1, the more common of the 2, constitutes 90% of all types of the neurofibromatoses and is one of the most common autosomal dominant disorders in humans, with an estimated incidence of approximately 1 in 3000 live births (Huson et al 1989). It has diverse manifestations in tissues that are primarily, although not exclusively, of neural crest origin, including some of its hallmark features of skin neurofibromas, café au lait spots, and Lisch nodules (Huson 1994a). It is also associated with a tendency to develop certain types of central and peripheral nervous system tumors (Huson 1994a).

2 Early portrayals of possible neurofibromatosis type 1 date as far back as the second century; a Hellenistic era Greek statue that may represent the first known medical depiction of neurofibromatosis type 1 has been identified (Zanca and Zanca 1980; Ragge and Munier 1994). The earliest convincing medical descriptions of what we now know to be neurofibromatosis type 1 occurred in the 18th century (Akenside 1785; Ludwig and von Tilesius 1793). However, Friedrich von Recklinghausen put the disorder in the medical lexicon with his correct identification in 1882 of the neural origin of its most common lesion, the neurofibroma (von Recklinghausen 1882). Following this important work, the disorder became known as von Recklinghausen disease. The significance of the café au lait spots as part of the disease was noted by Marie Bernard in 1896 (Huson 1994a). The familial occurrence of neurofibromatosis type 1 was recognized in 1847 by Virchow; the autosomal dominant inheritance pattern was suspected in 1918 by Preiser and Davenport (Huson 1994a). The mode of inheritance, high penetrance rate, and high frequency of new mutations, along with the broad spectrum of complications, were recognized by the 1950s (Huson 1994a). The description and story of Joseph Merrick, the "elephant man," chronicled by the physician Sir Frederick Treves and later dramatized on stage and in film, served to stimulate interest in neurofibromatosis type 1. Ironically, this patient probably did not have neurofibromatosis type 1, but suffered from the Proteus syndrome. Nevertheless, his story did bring neurofibromatosis type 1 to public attention (Huson 1994a). Increased clinical and laboratory research began in the 1970s, eventually leading to the localization of the neurofibromatosis type 1 gene on chromosome 17 as well as cloning of the gene (Barker et al 1987; Viskochil et al 1990; Wallace et al 1990). More recently, advancements in genetics and chromosomal mapping have led to greater understanding of the abnormal gene product in neurofibromatosis as well as the pathogenesis of the displayed phenotype. Clinical manifestations Presentation and course Neurofibromatosis type 1 is the most common form of neurofibromatosis; the 1988 National Institutes of Health Consensus Panel concluded that it was 1 of the 2 forms of neurofibromatosis that could be precisely classified at that time (Huson 1994a). Café au lait spots, peripheral neurofibromas, and Lisch nodules are the clinical manifestations of neurofibromatosis type 1 that most consistently occur in the majority of affected patients and form the basis of the National Institutes of Health Consensus Statement of diagnostic criteria for neurofibromatosis type 1 (Table 1) (Neurofibromatosis Conference Statement 1988). Table 1. Diagnosis of Neurofibromatosis Type 1* Six or more café au lait macules over 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals Two or more neurofibromas of any type or 1 plexiform neurofibroma Freckling in the axillary or inguinal regions Optic glioma Two or more Lisch nodules (iris hamartomas) A distinctive osseous lesion such as sphenoid dysplasia or thinning of long-bone cortex with or without pseudoarthrosis A first-degree relative (parent, sibling, or offspring) with neurofibromatosis type 1 by the above criteria. *The diagnostic criteria are met in an individual if 2 or more of the features listed are present. These criteria are not all-inclusive, and some features are age-dependent; definitive diagnosis may be delayed in younger patients. From a large survey by the National Neurofibromatosis Foundation International Database of neurofibromatosis type 1 patients under 21 years of age, 97% of patients had 2 or more of the cardinal criteria by 8 years of age, and all did so by 21 years. In contrast, 30% of neurofibromatosis type 1 patients under 1 year had only 1 of the cardinal criteria and

3 could not be diagnosed at that time, unless they had an affected relative (DeBella et al 2000). Café au lait spots. The lightly pigmented cutaneous macules are often the earliest feature of neurofibromatosis type 1 and among the most common, along with skin fold freckles, neurofibromas, and Lisch nodules. They may be present at birth or develop within the first 5 years of life, often in the first year (Korf 1990). There is no relationship between the location or number of café au lait spots and the development of other lesions or the severity of the condition. Persons unaffected by neurofibromatosis type 1 may have café au lait spots that are no different from those of patients with neurofibromatosis type 1 or neurofibromatosis type 2. However, in the experience of those who have examined large numbers of patients, the presence of more than 6 café au lait spots of a significant diameter has held up as an indicator of neurofibromatosis type 1. In an infant with no family history of neurofibromatosis type 1 who presents with multiple café au lait spots, the family should be told that neurofibromatosis type 1 is by far the most likely diagnosis, as familial café-au-lait spots on any other basis are exceedingly rare. Additional diagnostic criteria are almost always met by 10 years of age (Korf 1992). Conversely, in 1 series, nearly 100% of patients with neurofibromatosis type 1 had café au lait spots by 4 years of age (Huson 1994a). From 1 study of 1893 neurofibromatosis type 1 patients under 21 years of age, 99% had 6 or more café-au-lait spots greater than 5 mm in diameter by 1 year of age (DeBella et al 2000). Skin-fold freckling. Skin fold freckling is the other characteristic pigmentation, which usually appears later in childhood than do café au lait spots, most commonly between 3 and 5 years of age (Obringer et al 1989). This phenomenon is unique to neurofibromatosis type 1 and is best seen in the axillary and inguinal regions, but can also be seen in submammary regions in women, in the nape of the neck, or under the chin. In 1 study, the frequency of axillary and inguinal freckling has been reported to be greater than 80% by 6 years of age (Obringer et al 1989); in another study, there was a maximum frequency of 90% by 7 years of age. It was the most common feature, after caféau-lait macules, to appear in children and confirm the diagnosis (DeBella et al 2000). Because skin-fold freckling is the second most common age-dependent feature of neurofibromatosis type 1, it emerges as an important diagnostic criterion in early childhood and preadolescence (Korf 1992). Neurofibromas. Neurofibromas are spindle cell tumors that originate from a peripheral nerve sheath. The dermal or cutaneous neurofibroma is a discrete nodule with a characteristic violaceous color and soft gelatinous consistency, varying from 1 cm to several centimeters in diameter and lying within the dermis and epidermis (Huson 1994b). Dermal neurofibromas are present in most adults with neurofibromatosis type 1, but usually develop later than café au lait spots in the teenage years. From a large study of neurofibromatosis type 1 patients under 21 years of age, they were present in 48% of 10 year olds and 84% of 20 year olds (DeBella et al 2000). They arise primarily on the trunk, with predilection for the areolar area of the nipple in females; they can become papillomatous and may occasionally appear on the head and neck in patients who develop numerous lesions (Huson 1994b). Histopathologically, they are characterized by an extrafascicular proliferation of a loose population of spindle-shaped cells with delicate processes. They contain collagen fibers and myxoid degeneration and have low mitotic activity. The terminal nerve branch from which they originate frequently cannot be identified, but occasional axons can be seen within the tumor (Wiestler and Radner 1994). Some neurofibromas lie below the dermis (subcutaneous). The skin moves over these subcutaneous neurofibromas, which are firmer than cutaneous neurofibromas. Puberty is often associated with a major increase in number and size of the lesions, but no predictors of which patients will develop large numbers of these nodules have been identified. They rarely, if ever, undergo sarcomatous degeneration but may require removal when they occasionally become painful or pruritic (Riccardi 1992a). Nodular neurofibromas. These arise from major peripheral nerve trunks and are firmer, with more defined margins than dermal neurofibromas. With an estimated frequency of 5% in neurofibromatosis type 1, they are much less common; when present, they can rarely give rise to sensory or motor neurologic symptoms or pain (Huson 1994b). Plexiform neurofibromas. These are clinically and pathologically distinct from other neurofibromas. Most commonly, they are soft masses with ill-defined margins that vary from a few centimeters in diameter to those involving a large area of the body, and frequently have associated abnormality of the overlying skin (Huson 1994b). Histopathologically, they exhibit intrafascicular growth along major peripheral or spinal nerves and in the retroperitoneal and mediastinal compartments. They also may be discrete nodular tumors along the nerve or root, but are more often diffuse tumors and cause diffuse hypertrophy of the surrounding connective tissue, other soft tissue, and bone. The fascicular organization of the affected nerve segment is maintained and the individual fascicles may become enlarged by the neoplasm so that it resembles a nerve plexus (hence, the term plexiform neurofibroma) (Bouldin 1990). In affected

4 patients, they tend to occur at a younger age than dermal neurofibromas, and are almost always thought to be congenital lesions (Gutmann et al 1999); the larger, more significant ones are usually detected by 1 to 2 years of age (Huson 1994b). They are most frequently seen on the trunk, followed by the extremities and the head and neck, and are estimated to be present in 25% to 30% of patients by 18 years of age (Huson et al 1988). Plexiform neurofibromas often grow during early childhood but their growth is frequently self-limited. They are most often asymptomatic, but can cause significant cosmetic problems. Lesions involving the head and neck can become symptomatic, causing respiratory failure by growth into the airway, or compressing the spinal cord by growth into the cervical spine (Huson et al 1988). Unlike cutaneous neurofibromas, plexiform neurofibromas can undergo malignant transformation, and previous studies have shown that 3% to 5% of patients with neurofibromatosis 1 develop malignant peripheral nerve sheath tumors (Reed and Gutmann 2001). However, a study designed to assess the lifetime risk for developing malignant peripheral nerve sheath tumor revealed a much higher frequency ranging between 8% and 13% (Evans et al 2002). Because these lesions are more distinctive than dermal neurofibromas, only 1 is required to be a diagnostic criterion (Riccardi 1992a). Lisch nodules. Lisch nodules are iris hamartomas and nodular clumps of pigment cells in the iris of the eye. They usually appear in late childhood, after café au lait spots but before neurofibromas and, therefore, are useful for confirming a diagnosis of neurofibromatosis type 1 in children with café au lait spots, a negative family history, and no other features. Their frequency in neurofibromatosis type 1 has been estimated at 90% to 100% (Lewis and Riccardi 1981). In a large study of neurofibromatosis type 1 patients, Lisch nodules were present at a maximum frequency of greater than 70% of children by 10 years of age (DeBella et al 2000). A slit-lamp examination may be required for detection as well as to differentiate them from iris nevi (Lewis and Riccardi 1981). Optic pathway gliomas. The presence of an optic pathway glioma is a diagnostic criterion of neurofibromatosis type 1 because it is the single central nervous system tumor with a marked increased frequency in neurofibromatosis type 1 (Huson 1994b). Optic pathway gliomas are the most common type of central nervous system tumor seen in neurofibromatosis type 1 (Listernick et al 1989). Fifteen percent of hundreds of neurofibromatosis type 1 patients subjected to thin-cut, high-resolution CT scanning had tumors involving 1 or both optic nerves and sometimes the chiasm, but only one-third were symptomatic (Lewis 1990). A 1.5% prevalence rate of symptomatic optic gliomas was determined in 1 population study (Purvin and Dunn 1994). From a study of 1893 neurofibromatosis type 1 patients under 21 years of age, symptomatic optic glioma was diagnosed in the first year of life in 1% of neurofibromatosis type 1 patients and reached a maximum frequency of approximately 4% by 3 years of age (DeBella et al 2000). However, in a study of 90 children with initially symptomatic or incidentally found optic pathway gliomas, 36% were diagnosed in children over the age of 6 years, prompting the authors to recommend that all children aged 10 years or younger with NF1 undergo annual ophthalmologic examinations (King et al 2003). The majority of these tumors are low-grade astrocytomas. The consensus regarding their natural history is that, although these optic pathway gliomas are a somewhat heterogeneous group, many do not progress and remain asymptomatic. They may even regress spontaneously (Purvin and Dunn 1994; Allen 2000). The frequency of tumor progression is lower in some series than in others. The period of greatest risk for development of rapidly progressive tumors appears to be during the first 5 years of life (Listernick et al 1992). When they progress, visual symptoms are produced because the tumors enlarge and put pressure on the optic nerves-chiasm in a confined space (Lewis 1990). The optic tracts and radiations may also be involved by these tumors, and although this was found to be rare in a series of patients from 2 institutions, it appeared to signal much more significant and progressive visual symptoms (Liu et al 2004). The most common presenting symptoms are impaired visual acuity and visual fields and distortions of binocular fixation and dysconjugate eye movements (Riccardi 1992c). Extension into the hypothalamus is uncommon, but can lead to endocrine deficiencies or failure to thrive with a diencephalic syndrome (Riccardi 1992c). They rarely become malignant (Lewis 1990). However, in 1 study of 109 patients with neurofibromatosis type 1 diagnosed with low-grade gliomas, lesions located either in the chiasm or postchiasm were associated with an increased risk of progressive disease (Hernaiz Driever et al 2010). MRI characteristics typical of this tumor in patients with neurofibromatosis type 1 include a low-signal core and high-signal periphery of an enlarged optic nerve on T2- weighted imaging, or tubular thickening of 1 or both optic nerves. Globular lesions extending into hypothalamus are more characteristic of non-neurofibromatosis type 1 lesions (Purvin and Dunn 1994). Skeletal lesions. A skeletal lesion characteristic of neurofibromatosis type 1 is 1 of the diagnostic criteria in the National Institutes of Health Consensus Guidelines and has been described in up to 10% to 14% of patients with neurofibromatosis type 1 (Huson et al 1988) and are usually apparent in the first year of life (DeBella et al 2000). The

5 most consistent craniofacial bone dysplasia involves the sphenoid wing of the temporal bone. This is nearly always a unilateral and static lesion. Occasionally it will grow and breech the integrity of the orbit or distort the skull base, leading to impingement on the spinal cord. In a 2011 study, 85 patients with NF1 had lateral skull x-rays to assess any craniofacial bony abnormalities (Heerva et al 2011). Compared to age-matched healthy controls, NF1 patients had shortened mandible, maxilla, and cranial base. The results were only significant in adults, but suggest that the NF1 gene is involved in the growth of craniofacial bones. Thinning of a long-bone cortex with or without pseudoarthrosis (a "false joint" abnormality) is another characteristic feature of neurofibromatosis type 1 (Riccardi 1992b). It typically involves only 1 bone, usually the tibia, with medial deformity of the bone. It occurs most frequently in infancy, within the first year of life, and is associated with neurofibromatosis type 1 in 50% of patients who have it. One analysis demonstrated the differences in 72 patients with neurofibromatosis type 1, particularly their fracture rates and bone metabolism differences in comparison to their respective controlled matches (Tucker et al 2009). A statistically significant increase in bone fracture rate was indicated; there was also a decreased activated vitamin D and increased parathyroid hormone level in patients with neurofibromatosis type 1. Future studies will be needed to address the potential underlying molecular and cellular pathogenesis causing the above bone fracture and metabolic differences. Minor disease features. Two minor disease features of neurofibromatosis type 1 occur with a high frequency, but are not so specific that they can be used as diagnostic criteria. They are: (1) macrocephaly and (2) short stature (Huson 1994b). Macrocephaly (occipitofrontal diameter of skull greater than 2 standard deviations above the mean) unassociated with skull or specific brain abnormalities occurs in some series in 35% to 45% of neurofibromatosis type 1 patients (Huson 1994b). Short stature is reported in 30% of neurofibromatosis type 1 patients without specific hypothalamic, pituitary, skeletal, or other abnormalities (Huson 1994b). Many other clinical manifestations are not so characteristic as to be diagnostic criteria, but occur with increased frequency and produce much of the significant morbidity and mortality in neurofibromatosis type 1. These include neurofibromatosis type 1-associated malignant tumors, including peripheral nerve tumors (such as malignant schwannomas and neurofibrosarcomas) and non-neural tumors like pheochromocytoma, carcinoid, and adenocarcinoma of the duodenum. Many phenotypic associations (without clear causations) have been shown to occur in patients with neurofibromatosis. One such example comes from a study published in June 2007; the study compared approximately 100 patients with neurofibromatosis type 1 with appropriate age- and sex-matched controls and showed a statistically significant increase in the incidence of myopia amongst neurofibromatosis type 1 and type 2 patients, demonstrating an increase in refractive errors amongst neurofibromatosis type 1 and type 2 patients (Akinci et al 2007). Associations such as these are not part of the formal diagnosis of neurofibromatosis but may help further guide diagnosis and management. Intellectual handicaps and medical and surgical complications result from the growth of neurofibromas in specific organ locations and occur with increased frequency in neurofibromatosis type 1 (Huson 1994b). These will be discussed in greater detail the section on complications and prognosis. They develop in only a proportion of patients, but in an unpredictable fashion, even within the same family. Although 50% of patients with neurofibromatosis type 1 will have only cutaneous manifestations or Lisch nodules, 30% to 40% will develop 1 or more serious complication during their lifetime (Carey et al 1979). Prognosis and complications In addition to the major disease-defining manifestations of neurofibromatosis type 1 that constitute the 1988 National Institutes of Health Consensus Criteria for diagnosis, patients affected by neurofibromatosis type 1 have the potential for developing any of a large number of other clinical manifestations or complications that can affect virtually any body system. These conditions occur at an increased rate in individuals with neurofibromatosis type 1 compared with the general population, but are not characteristic enough to be diagnostic (Huson and Upadhyaya 1994). However, these complications cause much of the significant morbidity and mortality of neurofibromatosis type 1. They occur in only a

6 proportion of affected individuals, and their development is unpredictable even within the same family, making neurofibromatosis type 1 an extremely difficult disease to manage (Huson 1994b). Although more than 50% of individuals with neurofibromatosis type 1 will have only cutaneous neurofibromas, café au lait spots, or Lisch nodules, an estimated 30% to 40% will develop 1 or more of the serious complications in their lifetime (Carey et al 1979). A cross sectional study of 728 patients with NF1 examining cutaneous manifestations of NF1 revealed that the number of café-au-lait spots decreased with age whereas the cutaneous and subcutaneous neurofibromas increased with age (Duong 2011a). A recent study from Italy evaluated the mortality associated with NF1 over 12 years (Masocco et al 2011). Of the 6.75 million deaths over that time period, 632 had a diagnosis of NF1 on their death certificate, with a mean annual NF1-associated mortality of 0.92 per 1 million people. Compared to the general population, the mean age of NF1-associated deaths was approximately 20 years lower, with a more significant discrepancy among those less than the age of 40. A common morbidity not related to tumor growth was the 2-fold increase in obstructive chronic bronchitis among persons 40 years of age and older compared to the normal population. In a study of consecutive NF1 patients referred to the National French Referral Center for Neurofibromatoses, mortality was significantly increased in NF1 patients aged 10 to 40 years, more significant in females, with malignant nerve sheath tumor being the main cause of death (Duong et al 2011b). The major categories of severe complications associated with NF1 are discussed below. Disease-associated tumors. Malignant tumors in various locations account for the greatest proportion of morbidity and mortality in neurofibromatosis type 1. The frequency of malignancies is clearly increased, although the exact relative risks of specific types of tumors have not been optimally determined; the evidence for some associations is stronger than for others (Lefkowitz et al 1990). From several population studies, the overall likelihood of a neurofibromatosis type 1 patient developing some type of malignancy was estimated at approximately 3% (Huson et al 1989). A recently recognized manifestation of the NF1 phenotype are glomus tumors, benign tumors of the glomus body that cause severe paroxysmal pain secondary to changes in temperature or pressure. These are typically seen on the fingers and toes, but can be seen throughout the body and commonly appear as bluish subcutaneous nodules. Affected patients usually present with symptoms of severe paroxysmal pain, cold intolerance, and localized tenderness. One study estimated the prevalence of glomus tumors of the fingers in NF1 patients to be approximately 5% (Stewart et al 2010). Neural tumors. Neural tumors of several types, in addition to optic pathway tumors, have increased frequency in neurofibromatosis type 1 and occur in both the peripheral nervous system and the central nervous system (Rubenstein and Korf 1990). Peripheral nervous system malignant tumors, termed malignant peripheral nerve sheath tumors, which include neurofibrosarcomas, malignant schwannomas, and angiosarcomas, occur in neurofibromatosis type 1 with an estimated frequency of 1.5% from cross sectional studies (Huson et al 1989). However, a population-based longitudinal study of neurofibromatosis type 1 patients in Britain over a 13-year period from 1984 to 1996 determined an annual incidence of 1.6 per 1000 and a lifetime risk of 8% to 13%, much higher than previously estimated (Evans et al 2002). They can occur at any peripheral nervous system site but arise most frequently from plexiform neurofibromas (malignant degeneration virtually never occurs in dermal fibromas). Rapidly enlarging masses, especially if painful or causing motor or sensory symptoms, should be evaluated for possible malignancy. The prognosis of these tumors generally is poor, but wide excision where possible gives the best prognosis (Hughes 1994). In Kaplan-Meier analyses of the British population-based study, the 5-year survival from diagnosis for neurofibromatosis type 1 patients with malignant peripheral nerve sheath tumors was 21% compared to 42% for sporadic cases. Ultimately, 10% of the neurofibromatosis type 1 patients in this population died with malignant nerve sheath tumors (Evans et al 2002). However, surprisingly, from a review of 80 patients with malignant peripheral nerve sheath tumors followed at a single institution over the last 25 years, for the 18 associated with neurofibromatosis type 1, the 11 year survival was 85%, with no difference between the spontaneous tumors and those associated with neurofibromatosis type 1 (Cashen et al 2004). Analysis of the spectrum of neurofibromatosis type 1 gene mutations in individuals with neurofibromatosis type 1 demonstrated that those with large neurofibromatosis type 1 genomic deletions carried a substantially higher lifetime risk for developing malignant peripheral nerve sheath tumors (DeRaedt et al 2003). Because schwannomas have been postulated to be formed with abnormality of the neurofibromin tumor suppressor gene acting on the p19(arf)-mdm2-tp53 and p16ink4a-rb cell signaling cascades, targeted future therapies address curbing the amplification of growth factor receptor genes and, thereby, halting their transformation into malignant peripheral

7 nerve sheath tumors (Carroll and Ratner 2008). With regard to central nervous system tumors, the optic pathway glioma is the only central nervous system tumor with a marked increase in frequency in neurofibromatosis type 1 (Hughes 1994). The incidence of other central nervous system tumors has been presumed higher in neurofibromatosis type 1 than in the general population in previous reviews, but earlier estimates now appear contaminated by cases of neurofibromatosis type 2, in which there is a definitely increased number of meningiomas and gliomas (Hughes 1994). Current evidence is minimal for increased incidence of meningiomas in neurofibromatosis type 1 (Hughes 1994). The data regarding glial tumors other than optic pathway tumors are not as certain, but the overall incidence is probably not greater than 2% in neurofibromatosis type 1 patients (Huson and Upadhyaya 1994). Judging from anecdotal reports, cerebellar astroglial tumors are next in frequency to optic gliomas, and some series report a higher percentage of anaplastic than the more usual low-grade cerebellar astrocytomas seen in the general population (Ilgren et al 1985). Cerebral gliomas in neurofibromatosis type 1 may occur more frequently at unusual sites such as the thalamus and hypothalamus (Ilgren et al 1985). Brainstem gliomas have been reported to have a more insidious course and better response to radiotherapy than the typical tumor in the general population (Milstein et al 1989). Intrinsic spinal tumors, also usually gliomas, have been reported in neurofibromatosis type 1, although they are more frequent in neurofibromatosis type 2. They present with symptoms of progressive paraparesis and loss of pain and temperature sensation, and need to be distinguished from extradural cord compression by spinal root neurofibromas, best done with MRI (Hughes 1994). With the availability of cerebral MRI imaging, lesions with increased signal on T2-weighted images, so-called unidentified bright objects, have been detected in more than 30% of asymptomatic individuals with neurofibromatosis type 1. These are most often in basal ganglia, brainstem, and cerebellum, and may be more frequent in children and young adults (Hughes 1994). They appear to behave as benign, nonprogressive lesions, and most likely represent areas of increased water content in association with gliosis (Gutmann 1998). Histopathologic evaluation of these T2 signal abnormalities during the autopsy of 3 children with neurofibromatosis type 1 found that they corresponded to pathologic findings of areas of vacuolar or spongiotic change. The fluid-filled vacuoles were thought to explain the occurrence of high signal intensity demonstrated on T2-weighted images (DiPaolo et al 1995). Non-neural malignant tumors. Completely reliable estimates of the frequency of all non-neural malignant tumors with neurofibromatosis type 1 are not available. Cross-sectional and retrospective cohort studies give credible evidence for valid associations of neurofibromatosis type 1 and pheochromocytoma, duodenal carcinoid, adenocarcinoma of the ampulla of Vater, certain nonlymphocytic leukemias in children, particularly xantholeukemia, and possibly rhabdomyosarcoma (Mulvihill 1994). Intellectual impairment. Intellectual impairment, usually mild-to-moderate, has long been recognized as a complication of neurofibromatosis type 1. Research with psychometric and behavioral testing determined that patients may have low intelligence quotients, specific learning disabilities, or a combination. Estimates of mental retardation (IQ less than 70) were 8% to 10% in neurofibromatosis type 1 patients compared to 3% in the general population (Riccardi and Eichner 1986). Specific learning disabilities were 40% to 60% compared to 6% to 10% in the general population (Riccardi and Eichner 1986; North et al 1997). These included visual-spatial problems, language disorders, memory dysfunction, and attention deficit disorders (Ferner 1994a). Some groups have found a correlation between the presence of the MRI T2 signal abnormalities, termed unidentified bright objects, found in up to 30% of neurofibromatosis type 1 patients, and a left shift in the full-scale IQ. Children with MRIs showing unidentified bright objects had mean IQ scores of 85, compared with their unidentified bright object negative counterparts with mean IQ scores of 100 (North et al 1994). In a study of cognitive function in 100 patients with neurofibromatosis type 1 compared with 100 age, sex, and socioeconomic- matched healthy controls, scores of neurofibromatosis type 1 patients with no T2 signal abnormalities were at the mean, but those with T2 abnormalities were significantly depressed (Feldmann et al 2003). In 1 report, a correlation was demonstrated between the presence of UBOs specifically in the thalamus, and learning disabilities in children (Moore et al 1996). The majority of these T2 abnormalities are known to resolve as the child ages. From a prospective longitudinal Australian study, the T2 abnormalities in childhood predicted poor cognitive abilities, which did not change when the abnormalities disappeared. Accordingly, the best predictors of cognitive dysfunction in adulthood were MRI scans done before 18 years of age. Thus, there is a limited window (before 18 years of age) in which the presence of T2 signal abnormalities are predictors of cognitive function (Hyman et al 2003). Studies have shown an increased prevalence of attentional deficits in children with NF1 (63% to 67%), with 38% to

8 50% of children meeting the criteria for attention deficit hyperactivity disorder (ADHD). Furthermore, these studies have demonstrated the benefit of methylphenidate in tests of attention, yet the pathophysiology relating NF1 and inattention remain unclear. Although ADHD has been often used in the literature to describe the executive functioning deficits experienced by children with NF1, on the Test of Variables of Attention, a neuropsychological measure of sustained attention, the performance of children with both NF1 and ADHD were comparable with children who had NF1 alone, suggesting that children with NF1 can experience attention problems even though they do not meet diagnostic criteria for ADHD. Similarly, children with NF1 alone and those with NF1 and ADHD both appear to have problems with planning, even when controlling for IQ or visual-spatial skills. This would suggest that children with NF1 experience problems with executive functioning that are not wholly accounted for by the behavioral features of ADHD (Templer et al 2013). Using NF1 optic glioma mice, researchers were able to demonstrate reduced exploratory and attentional behaviors in these mice compared to wild-type mice (Brown et al 2010). This behavior was able to be improved with dopamine administration and, furthermore, researchers were able to localize the abnormality to reduced dopamine in the striatum. Decreased synaptic plasticity and impaired attention has been associated with loss of function mutation of the neurofibromin gene in NF1. A recent study looked at the use of lovastatin. It found that lovastatin use in patients with NF1 increased synaptic plasticity as well as phasic alertness (Mainberger et al 2013), indicating a potential use of lovastatin in this unique patient population. Speech dysfluencies have also been identified with increased frequency in patients with neurofibromatosis type 1, cited by some to have an incidence between 30% and 40%. A Dutch study that sampled 21 adults with neurofibromatosis type 1 found an increased incidence of dysfluencies, namely interjections (59%), with (less commonly) revisions, prolongations, and incomplete phrases. Although stuttering may be present in these patients, this occurs much less commonly as the other dysfluencies previously cited (Cosyns et al 2010). Fine and gross motor skills appear to be delayed in children with NF1 as well. In a study using the Bruininks-Oseretsky Test (BOT 2), a reliable measure of motor proficiency, researchers found that NF1 children, compared to age- and gender-matched controls, had the most significant deficiencies in balance and strength subtest scores, followed by running speed, agility, fine motor precision, bilateral coordination, and fine motor integration (Johnson et al 2010). These deficiencies may contribute to decreased physical activity in NF1 children, possibly resulting in the increased osteopenia and fracture rate seen. This study suggests the need for physical therapy, focusing on multiple aspects of motor proficiency to assist NF1 children. Epilepsy. The conclusion from analysis of all reported series of seizures in neurofibromatosis type 1 patients, including hospital-based populations and cases with well-known structural nervous system causes of seizures, is that neurofibromatosis type 1 probably carries a small (2% to 5%) overall increased risk of epilepsy (Hughes 1994). These cases are partially accounted for by macroscopic abnormalities, and the residual risk may be secondary to microscopic abnormalities of the cortex, which are also described as a possible basis for the intellectual impairment in neurofibromatosis type 1. In a more recent study looking at epilepsy in individuals with neurofibromatosis type 1, it was found that maternal inheritance of NF1 was more commonly associated with the incidence of seizures in this population. Over half of the individuals with seizures had focal seizures, as opposed to generalized seizures. Interestingly, in 21% of patients with initial normal MR brain imaging, a new structural abnormality was revealed when reimaged at seizure onset (Ostendorf et al 2013). Patients are traditionally managed with either antiepileptic medications or epilepsy surgery. Cerebrovascular disease. Anecdotal cases of smooth intrinsic stenosis or occlusion of major cerebral vessels, most frequently supraclinoid internal carotid, or proximal anterior or middle cerebral arteries in association with moyamoya type collateralization, have been reported in neurofibromatosis type 1, but the true incidence is unknown (Hughes 1994). These patients often presented with stroke in childhood. An increased prevalence of stroke from presumed atherothrombotic cerebrovascular disease has been reported in neurofibromatosis type 1 (Riccardi 1981). However, this must be interpreted cautiously, because hypertension, for which neurofibromatosis type 1 patients are at increased risk, accounts for some cases and the moyamoya constriction may be responsible for others (Hughes 1994). In a recent retrospective review, the prevalence of cerebral vasculopathy was reidentified in pediatric patients with NF1, finding a 7% minimum prevalence in their patient population (Kaas et al 2013). Ten cases of cerebral aneurysms and subarachnoid hemorrhage have been reported with neurofibromatosis type 1. Four had internal carotid constriction, and the bleeding may have been related to blood vessel abnormalities rather

9 than to berry aneurysms (Hughes 1994). Two unrelated cases of young children with NF1 have been reported with a characteristic vasculopathy that, in adults, is rarely associated with fatal coronary artery occlusion but, in these children, resulted in sudden cardiac death (Kanter et al 2006). Spinal meningoceles. Spinal meningoceles, which are herniations of the thecal sac, occur with an increased frequency in neurofibromatosis type 1, usually in the thoracic region as incidental findings on plain x-rays (Hughes 1994). They can cause a paravertebral mass that scallops vertebrae and are hard to distinguish from "dumbbell" neurofibromas of spinal roots. Occasionally they cause spinal nerve and spinal cord symptoms or headache attributable to slow leakage of cerebrospinal fluid (Hughes 1994). Psychosocial and psychiatric pathology. Several studies have identified problems that constitute a significant psychosocial burden experienced by individuals with neurofibromatosis type 1 (Ablon 1992). The extreme unpredictability of the disease can result in persistent chronic anxiety about what may lie ahead. Potential or actual cosmetic disfigurement associated with neurofibromatosis type 1 is particularly difficult to cope with in a society where so much value is placed on appearance. The high rate of various types of learning problems may make schooling an unhappy, unsuccessful experience. Cognitive problems may compound further the difficulty of dealing with the psychological burden of the disease (Ablon 1992). Finally, inadequate or inaccurate information given to affected individuals about neurofibromatosis type 1 can have a profound negative influence on their ability to cope with the disease (Huson and Upadhyaya 1994). It has been suggested that patients with neurofibromatosis type 1 have more psychiatric disease than the rest of the population (Hughes 1994). However, several studies have shown no higher incidence of diagnosed psychiatric illness, including psychosis and organic depression, than in the general population (Hughes 1994). One study did show that children and adolescents with NF1 have a reduced quality of life as well as more psychological adjustment problems compared with healthy children (Graf et al 2006). In a questionnaire about disease visibility and body image of 228 adult NF1 patients, there was an associated negative body image in NF1 patients, even compared to other disfiguring diseases. Psychotherapeutic treatment is recommended for those patients with a highly negative body image as it may more effectively help to reduce their psychological burden and lead to improved quality of life (Granström 2012). Cardiovascular system. Hypertension is the most significant general medical problem in neurofibromatosis type 1, affecting approximately 6% of patients. It may represent essential hypertension, but there is also an increased incidence of pheochromocytoma, coarctation of the aorta, and renovascular hypertension (Ferner 1994b). Respiratory system. Plexiform neurofibromas of the head and neck may cause respiratory problems by their growth into the upper airway. Neurofibromas, ganglioneuromas, and peripheral nervous system tumors characteristic of neurofibromatosis type 1 may occur in the chest, most frequently in the mediastinum or occasionally in the lung. They are most often benign and asymptomatic, but may cause cough and dyspnea, or occasionally cause progressive problems because they are malignant (Mulvihill 1994). Scoliosis associated with neurofibromatosis type 1 may decrease lung volumes and impair mechanical ventilation (Ferner 1994b). Pulmonary hypertension is a severe complication of NF1, initially described in patients with advanced parenchymal disease. In a study looking at 8 patients with NF1 with signs of pulmonary hypertension, researchers identified that even patients without evidence of parenchymal disease develop pulmonary hypertension (Montani et al 2011). The disease appears to be characterized by late onset, female predominance, resulting in significant functional impairment. Standard therapies for pulmonary hypertension appear to have only a modest effect on disease symptomatology and progression. Gastrointestinal system. Carcinoid tumors have an increased frequency in neurofibromatosis type 1 and have a striking tendency to occur in the duodenum near the ampulla of Vater (Mulvihill 1994). More than 50% of duodenal tumors occur in patients with neurofibromatosis type 1, usually in adulthood. Because carcinoid tumors and pheochromocytoma may occur in the same patient, the duodenum should be examined in any neurofibromatosis type 1 patient undergoing surgery for pheochromocytoma.

10 One report estimated that 1% of mostly adult neurofibromatosis type 1 patients develop gastrointestinal neurofibromas that can cause symptoms ranging from pain and constipation to obstruction and perforation (Huson et al 1988). Ganglioneuromatosis is a rare proliferative condition of the myenteric plexus of the gastrointestinal tract in neurofibromatosis type 1, which also presents with abdominal pain and constipation (Ferner 1994b). Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm of the GI tract. Studies have indicated that GISTs occur up to 150 times more frequently than in the general population. Typically non-nf1 GISTs are associated with activation of KIT or PDGFRA tyrosine kinases; however, this is not the case with NF1-associated GISTs (Wang et al 2011). Oral cavity. NF1 has been known to affect the oral cavity through multiple manifestations. Previous studies have identified oral soft tissue alterations in approximately 76% to 92% of patients, with 25% of patients having intraoral tumors, most commonly of the tongue but also including the buccal mucosa, alveolar ridge, gingiva, lips, palate, floor of the mouth, and the pharyngomaxillary space. Other previously reported findings of the oral cavity included macroglossia and enlarged papillae of the tongue. A recent study looked at 103 individuals with NF1 and noted 76 individuals as having oral tissue alterations (Jouhilahti et al 2012). This most commonly included mucosal tumors, overgrowths of gingival soft tissue, and prominent lingual papillae. Oral mucosal tumors comprised 37% of all patients studied, and most commonly involved the tongue. Compared to the numerous cutaneous neurofibromas usually found, oral neurofibromas are usually solitary or few in number. Urogenital tract. Neurofibromas in the retroperitoneum may compress the upper urinary tract, causing hydronephrosis, or compress the bladder, causing micturition problems (Ferner 1994b). Neurofibromas affecting the external genitalia have psychosexual implications, and rarely plexiform neurofibromas have caused hypertrophy in infancy, causing ambiguous genitalia. Malignant rhabdomyosarcomas can arise in the pelvis in neurofibromatosis type 1 patients (Huson 1994b). Skeletal system. Skeletal bony abnormalities are common with neurofibromatosis type 1, causing functional or cosmetic involvement in 10% of patients and radiologic abnormalities in nearly 40% (Fairbanks 1994). The skeletal changes seem to be due to defective neuroectodermal-mesodermal elements rather than pressure per se from soft tissue masses. The most common skeletal changes in neurofibromatosis type 1 are the spinal deformities of kyphosis and scoliosis and the long-bone deformation and pseudoarthroses that are the characteristic skeletal diagnostic features of neurofibromatosis type 1 (Fairbanks 1994). Scoliosis in children with neurofibromatosis type 1 often occurs at an earlier age than in the general population, and may more often require spinal fusion (MacEwen 1990). Spinal deformities occur in up to 50% of patients with NF1. Scoliosis is the most common osseous complication of NF1, affecting 21% of patients, and may be nondystrophic or dystrophic. Nondystrophic scoliosis has a presentation similar to that of adolescent idiopathic scoliosis, although with an earlier onset; it may progress to dystrophic scoliosis, especially if the patient presents before the age of 7 years (Patel 2012). The congenital thinning and bowing of long bones, most often of the tibia, predisposes to fractures, which have a tendency not to heal, forming pseudoarthroses (MacEwen 1990). Bone overgrowth resulting in gigantism of digits, hands, or extremities is seen in neurofibromatosis type 1 and may or may not be associated with plexiform neurofibromas (MacEwen 1990). Clinical vignette A 3-year-old boy was referred to an ophthalmologist because of the new onset of a "lazy" left eye that had been noticed by his parents to be drifting inward intermittently over the previous 2 months. His parents reported that he also seemed to be sitting much closer to the television than he had previously. On examination, he had decreased visual acuity in both eyes (left = 20/400 and right = 20/30) with a left afferent pupillary defect, temporal visual field deficits, a pale optic disc on the left greater than on the right, and the presence of Lisch nodules in both irises. His general examination was notable for 7 to 8 café au lait spots distributed over the skin of his chest, back, and extremities. An MRI of his brain showed a gadolinium-enhancing mass centered in the optic chiasm and extending into the proximal portions of both optic nerves posteriorly into the proximal portions of the optic tracts. This had the typical appearance of an optic pathway glioma and he was diagnosed with neurofibromatosis type 1 on the basis of this tumor, the more than 6 café au lait spots greater than 5 mm in diameter, and the Lisch nodules. His mother also had