Clinical manifestations

Presentation and course

	• Café-au-lait spots, Lisch nodules, and neurofibromas are the clinical manifestations that most consistently occur in the majority of patients.
	• Over 80% of adults with neurofibromatosis 1 have Lisch nodules, choroidal abnormalities, and neurofibromas; about 90% have cutaneous neurofibromas (appearing as a soft sessile or pedunculated nodules), 20% have subcutaneous neurofibromas, and 30% to 50% have plexiform neurofibromas (appearing as either firm, linear, and beaded nodules or poorly defined elastic masses with overlying hyperpigmented skin loss of elasticity).
	• Plexiform neurofibromas have a high growth period in early childhood but have little growth in adulthood. They have a 10% lifetime risk of malignant transformation.
	• Approximately 15% of patients with neurofibromatosis 1 have optic pathway gliomas, but only about one third become symptomatic, predominantly before 7 years of age.
	• Up to 80% of children with neurofibromatosis 1 experience cognitive and behavioral difficulties involving different domains. Specific learning disabilities and attention-deficit/hyperactivity disorder are both found in 40% of children.

Hallmark signs and symptoms

Neurofibromatosis 1 is characterized by diverse cutaneous, neurologic, skeletal, vascular, and neoplastic manifestations, most of which are age-dependent (Table 2). Café-au-lait spots, pseudoarthrosis, and externally visible plexiform neurofibroma can be apparent within the first year of life. Choroidal abnormalities, freckling, optic gliomas, and scoliosis often occur by 7 years of age. Cutaneous neurofibromas and Lisch nodules tend to appear in teenage or young adult years. Malignancies and paraspinal neurofibromas mostly commonly occur in adults. Café-au-lait spots, neurofibromas, choroidal abnormalities, and Lisch nodules are the clinical manifestations that most consistently occur in the majority of patients and form the basis of the revised diagnostic criteria for neurofibromatosis 1 (Table 1) (63).

Table 2. Main Clinical Manifestations by Age Group (Approximate Incidence Among Neurofibromatosis 1 Individuals)

Birth (congenital)
	• Plexiform neurofibroma (head and neck) (25% to 50%) (14) • Tibial dysplasia/sphenoid wing dysplasia (5% to 12%) (50; 25) • Café-au-lait spots (50)
Preschool (0 to 7 years old)
	• Café-au-lait spots (80% by age 1) (50) • Intertriginous freckling (50% by age 10) (07) • Optic pathway glioma (15%) (50) • Brainstem glioma (< 5%) (07) • Pseudoarthrosis (2% to 5%) (50) • Macrocephaly (> 50%) (50) • Intellectual disability (IQ < 70 (4% to 8%) (50) • Attention-deficit/hyperactivity disorder (40%) (109) • Juvenile xanthogranulomas (30% < age 2) (49) • Juvenile myelomonocytic leukemia (1 out of 300) (37) • Embryonal rhabdomyosarcoma (1%) (37) • Choroidal abnormalities (80%) (74)
School (7 to 12 years old)
	• Lisch nodules (70% by age 10) (34) • Neurofibromas (50%) • Plexiform neurofibroma (abdominal) • Osteoporosis (50%) (94) • Short stature (30%) (50) • Specific learning disabilities (40%) (109)
High-school (12 to 18 years-old)
	• Neurofibromas (> 80% by age 20) (34) • Scoliosis (10% to 30%) (50) • Hypertension (4% to 16%) (50; 91) • Central nervous system tumors
Adults
	• Café-au-lait spots (95%) • Lisch nodules (90%) (110) • Neurofibromas (> 80% by age 20) (34) • Malignant central nervous system tumors (1%) • Malignant peripheral nerve sheath tumors (10%) (50) • Gastrointestinal stromal tumors (6%) (37) • Catecholamine-secreting tumors (including pheochromocytoma) (2%) (14) • Hypertension (5% to 16%) (50; 91) • Renal artery stenosis (1%) (110)

Cutaneous manifestations

In addition to the classic skin manifestations of neurofibromatosis 1 (café-au-lait spots, freckling, and neurofibromas), the presence of other common skin manifestations such as juvenile xanthogranulomas and nevus anemicus may be of high predictive value in patients with typical café-au-lait spots but without definitive diagnosis.

Café-au-lait spots. Café-au-lait spots are flat uniformly hyperpigmented macules with a smooth regular border. Up to 15% of the normal population has one to three café-au-lait spots. However, the presence of six café-au-lait spots is highly suggestive of neurofibromatosis 1, especially when the diameter criteria are met (> 5 mm prepuberty and > 15 mm postpuberty). Café-au-lait spots are probably the most important clinical criterion because they are usually the earliest manifestation of neurofibromatosis 1 and are present in almost all individuals with neurofibromatosis 1. Café-au-lait spots are often present at birth, increase in number during the first few years of life, and then stabilize over time. By the first year of life, over 90% of patients with neurofibromatosis 1 have sufficient café-au-lait spots to meet the diagnostic criteria (34; 49). Café-au-lait spots are darker during childhood, tend to fade later in life, and may be difficult to distinguish in older individuals. They can be found anywhere on the body, but usually not on the face. There is no association between the number of café-au-lait spots and the development of other lesions or the severity of the condition (49).

Skinfold freckling. Skinfold freckling (Crowe sign) describes small (1-3 mm) hyperpigmented lesions of light brown color symmetrically clustered in the intertriginous areas. Axillary or inguinal freckles represent one of the seven diagnostic criteria, although freckles can also be found elsewhere (face, under the chin, submammary region, trunk). After café-au-lait spots, freckles are the second most common feature to appear in children and confirm the diagnosis (34). Unlike café-au-lait spots, they are not usually present at birth and tend to develop during childhood (age 2 to 5 years and older). They are present in approximately 50% of children with neurofibromatosis 1 by 10 years of age (07) and in over 80% of adults with neurofibromatosis type 1 (14). As their histological characteristics are identical to those of café-au-lait spots, some authors argue that they should be combined in the same diagnostic criteria (49).

Juvenile xanthogranulomas. Juvenile xanthogranulomas are reddish or yellowish skin papule or nodules, usually solitary (about 70%), found on the head, neck, or upper trunk of young children. Juvenile xanthogranulomas is present in approximately 30% of children with neurofibromatosis 1 younger than 2 years old, and spontaneously regress 1 to 5 years after onset; they are found in about 0.5% of adults with neurofibromatosis 1 (49). Juvenile xanthogranuloma represents the most common form of non-Langerhans cell histiocytosis. Its presence was previously thought to confer a greater risk of juvenile myelomonocytic leukemia, although this association has not been supported by other studies, and it might be coincidental as both juvenile xanthogranulomas and juvenile myelomonocytic leukemia are associated with neurofibromatosis 1 (49; 78).

Nevus anemicus. Nevus anemicus is a disorder that causes benign, pale whitish, irregular macules clinically apparent during bathing, fever, crying, or after mild rubbing of the area, thought to be due to absence of focal response to catecholamine action (49). Histologically, the macules are indistinguishable from normal skin. Nevus anemicus can manifest anywhere on the body, but most commonly on the presternal region, and are present in up to 50% of individuals with neurofibromatosis 1 (49). Taken together, juvenile xanthogranulomas and nevus anemicus are present in most children with neurofibromatosis 1 younger than 2 years of age. Because they are found in 80% of patients with insufficient diagnostic criteria, they might represent helpful criteria in improving the early diagnosis of neurofibromatosis 1 in infants and young children (14).

Neurofibromas. Neurofibromas are benign, WHO grade 1 peripheral nerve sheath tumors consisting of neoplastic, well-differentiated Schwann cells intermixed with nonneoplastic elements (perineural cells, fibroblasts, mastocytes, extracellular matrix, axons, or endothelial cells) that can occur throughout the peripheral nervous system. Approximately 80% of 20-year-old patients with neurofibromatosis 1 have neurofibroma (34; 50). The classification of neurofibroma varies according to different authors, and clinical and histological terms are often mixed. They are sometimes being classified as superficial, deep, and plexiform neurofibromas, and sometimes as cutaneous (or dermal), subcutaneous, and plexiform neurofibromas. An easier clinically based classification has been proposed (Table 3) (49). The presence of at least two neurofibromas of any type or of one plexiform neurofibroma is a diagnostic criterion for neurofibromatosis 1.

Cutaneous (or dermal) superficial neurofibroma is the most common tumor type that occurs with neurofibromatosis 1, affecting over 90% of individuals with neurofibromatosis 1 (14). They arise from a single peripheral nerve lying within the dermis or epidermis. They consist of soft gelatinous sessile or pedunculated (“wart-like”) nodules measuring 1 to 2 cm that move with the skin on examination and are not tender, often with an overlying violaceous discoloration. Cutaneous neurofibromas can be found at any site but have a predilection for the trunk and the periareolar region, in women. They usually appear during early adolescence and tend to increase in size and number with age, most prominently during the adolescence and pregnancy periods (84). Cutaneous neurofibromas are rarely painful, but pruritus is often associated with accelerated growth, and is attributed to an abundance of mastocytes within the lesion (49). Although cutaneous neurofibroma are benign and do not carry an increased risk of malignant transformation, they are frequently associated with significant cosmetic impact or functional problems and may need to be surgically removed.

Plexiform neurofibromas affect 30% to 50% of individuals with neurofibromatosis 1 (14) and are almost pathognomonic of neurofibromatosis 1 (70), or NF1 mosaicism. They are histologically similar to cutaneous neurofibromas but involve multiple nerve fascicles or larger nerve plexus and have more extracellular matrix (110). As the individual fascicles become enlarged within the neoplasm, it resembles a nerve plexus (hence, the term plexiform neurofibroma). Plexiform neurofibromas may be located superficially within subcutaneous tissue, associated with overgrowth of skin and soft tissues, and be palpable, or they may be entirely internal (or “deep”), involving orbit, spinal roots, or viscera (Table 3). They occur most commonly in the head and neck region (30% to 50%), trunk/paraspinal region (30%), and the extremities (25%) (18; 75). Plexiform neurofibromas have a high growth period in early childhood but have little growth in adulthood; spontaneous regression is extremely rare (18). An ongoing natural history study has shown that most patients with neurofibromatosis 1 and plexiform neurofibroma have at least one associated morbidity, most commonly pain, followed by disfigurement and motor dysfunction, which tend to worsen over time in the absence of effective treatment (09).

Subcutaneous plexiform neurofibromas can be nodular or diffuse on palpation (Table 3). Nodular subcutaneous plexiform neurofibromas are rubbery, firm, linear, and beaded nodules that follow the peripheral nerve (49), and they can sometimes be confused with swollen lymph nodes on examination. They can rarely give rise to sensory or motor symptoms. Diffuse subcutaneous plexiform neurofibromas are poorly defined elastic masses, sometimes referred as to “bag-of-worms”, often associated with overlying hyperpigmented skin, which has lost normal elasticity. About 5% of babies with neurofibromatosis 1 have diffuse subcutaneous plexiform neurofibromas, most commonly affecting the head and neck region. Recognition of such tumor is important as it may lead to early diagnosis of neurofibromatosis 1 in a baby who otherwise only displays café-au-lait spots (37).

Deep plexiform neurofibromas can also be nodular or more diffuse and can present at any site. They are usually present at birth (congenital) but often go unnoticed in clinical examination.

Although the majority of plexiform neurofibromas remain benign, they are associated with high morbidity from disfigurement and local invasion to bones leading to pain and deformation, as well as internal organ, trachea, or vascular compression (07). Importantly, it is important to note that plexiform neurofibromas have a 10% lifetime risk of malignant transformation to malignant peripheral nerve sheath tumors (70), with a mean age at presentation in the mid-30s (07).

Table 3. Clinical Classification of Neurofibromas

Superficial neurofibromas (palpable)
	• Cutaneous (or dermal) • Subcutaneous (nodular or diffuse)*
Deep (internal) neurofibromas (not palpable)*
	• Visceral neurofibroma • Spinal neurofibroma • Orbital neurofibroma
(49) *These usually correspond to plexiform neurofibromas according to the current clinical criteria of the National Institutes of Health (81).

Ocular manifestations

Lisch nodules. Lisch nodules are iris hamartomas, nodular proliferations of melanocytes and fibroblasts. They appear as reddish-brown spots in the iris of pale-eyed people and as hypopigmented spots in brown eyed people. Lisch nodules are most commonly found in the lower pole of the iris and do not affect vision (110). They may be seen with a direct ophthalmoscope but slit-lamp examination allows for better detection and also distinguishes them from iris nevi. Lisch nodules usually appear in late childhood, after café-au-lait spots and skinfold freckling. They are present in less than 10% of children younger than 6 years, in over 70% of children by 10 years of age (34), and in over 80% of adults (14).

Optic pathway gliomas. Optic pathway gliomas are typically WHO grade 1 pilocytic astrocytomas that can arise anywhere along the visual pathway, including the optic nerve (anterior visual pathway), the optic chiasm, or optic tract (posterior visual pathway). In the general pediatric population, optic pathway gliomas represent less than 5% of CNS tumors and about 30% of all gliomas (47). In the neurofibromatosis 1 pediatric population, optic pathway glioma is the most common type of CNS tumor, representing over 60% of all CNS tumors and 85% of gliomas (49).

About 50% of optic pathway gliomas are neurofibromatosis 1-associated, whereas approximately 15% of individuals with neurofibromatosis 1 have an optic pathway glioma (41). Compared with sporadic optic pathway gliomas, neurofibromatosis 1-associated optic pathway gliomas more frequently involve the anterior visual pathway, are smaller, less symptomatic, and have a more favorable course. Bilateral optic nerve gliomas are almost exclusively seen in patients with neurofibromatosis 1. Among the neurofibromatosis 1 population, mean age at diagnosis is about 4 years old, and 50% are detected before 10-years-old, with no sex predilection (41). Children with coexisting atopic conditions seem to develop less optic pathway glioma (28). Optic nerve tortuosity, but not nerve or sheath thickening, has been associated with optic pathway glioma development among patients with neurofibromatosis 1 (65).

Only about one third of patients with neurofibromatosis 1 with optic pathway gliomas become symptomatic, predominantly before 7 years of age (105). However, symptomatic optic pathway gliomas in adolescence and adulthood have been described (from one to 44 years of age) (41). Identified risk factors for vision loss include posterior optic pathway glioma, age younger than 2 years at presentation, and female gender; although each of these at this time lacks sufficient sensitivity and specificity to be incorporated into clinical decision management strategies (28). Symptoms depend on tumor location. Anterior visual pathway gliomas may result in a compressive optic neuropathy presenting with decreased visual acuity and color vision, relative afferent pupillary defect, optic disc edema (or more chronically optic pallor and atrophy), or with proptosis, strabismus, or nystagmus. Posterior visual pathway gliomas may result in symptoms from obstructive hydrocephalus, impaired vision from visual field cut (chiasmatic and optic tract lesions), or in a diencephalic syndrome with failure to thrive or endocrinopathies (hypothalamic-chiasmatic lesions) (41). Posterior visual pathway gliomas cause increased morbidity, with 62% associated visual loss (compared with 32% in anterior optic pathway gliomas) and 10% to 40% associated endocrinopathies, most commonly precocious puberty (105). Natural history of neurofibromatosis 1-associated optic pathway gliomas is otherwise impossible to predict, with spontaneous regression reported (41). Chiasmatic gliomas tend to have a more aggressive course both by invading the hypothalamus and by occluding the foramen of Monro. Optic pathway glioma does not affect overall survival of children with neurofibromatosis 1, unlike in children with sporadic optic pathway glioma (37).

Glaucoma. Glaucoma affects approximately 23% to 50% of patients with neurofibromatosis 1 and commonly occurs ipsilateral to an upper eyelid plexiform neurofibroma. Glaucoma is typically unilateral and diagnosed before the age of 3. The pathophysiology included direct anterior chamber angle infiltration by neurofibroma, secondary angle closure from neurofibromatous thickening, fibrovascularization, and developmental angle abnormalities (107). Although the majority presents in children, adults should continue to have regular eye examinations to screen for glaucoma in addition to retinal vasoproliferative lesions that could lead to neovascular glaucoma (107).

Retinal microvascular abnormalities. Retinal microvascular abnormalities affect approximately 30% of patients with neurofibromatosis 1 and are associated with age. Retinal microvascular abnormalities are detectable with conventional ophthalmoscopy, optical coherence tomography (OCT), and fluorescein angiography (80). Their clinical significance remains unknown (74).

Congenital abnormalities of the retinal vasculature. Congenital retinal vasculature abnormalities such as supernumerary optic disc vessels or triple branching of retinal vasculature have been reported in over 90% of patients with neurofibromatosis 1 and are assumed to be congenital and nonprogressive. These findings have estimated high sensitivity, specificity, and diagnostic accuracy, although larger prospective studies are needed to confirm these results (74).

Choroidal abnormalities. Over 80% of patients with neurofibromatosis 1 are found to have choroidal abnormalities representing hamartomatous thickening (ganglioneuroma) on modern imaging techniques (114; 82). These ovoid bodies in the outer choroid are completely asymptomatic and grow in number and surface with age (74). As choroidal abnormalities are highly specific findings for neurofibromatosis 1, and because they occasionally precede the appearance of Lisch nodules, they have been integrated into the revised neurofibromatosis 1 diagnostic criteria as an alternative to the presence of iris Lisch nodules (63). Their presence allows to differentiate neurofibromatosis 1 from Legius syndrome and emphasizes the importance for physicians to obtain optical coherence tomography imaging when evaluating patients with suspected neurofibromatosis 1, as they are not detectable by conventional ophthalmoscopic examination (74).

Hyperpigmented spots. Hyperpigmented spots visible at fundus examination have been described as a new ocular sign in 60 out of 249 (24%) patients with neurofibromatosis 1 (79). Hyperpigmented spots share a similar appearance and location to choroidal abnormalities, presenting as rounded, hyperpigmented areas with blurred margins predominantly distributed to the posterior pole (74).

Skeletal lesions

Skeletal features of neurofibromatosis 1 include focal anomalies such as bony dysplasia, bony erosion or demineralization, nonossifying fibromas, and scoliosis, and more generalized anomalies such as osteopenia/osteoporosis, short stature, and macrocephaly. Collectively, the incidence of osseous defect in the neurofibromatosis 1 population is estimated to be as high as 70% (94).

Bony dysplasia includes splayed ribs, vertebral anomalies, sphenoid or mandible hypoplasia, long bone dysplasia, and pseudoarthrosis. Sphenoid wing dysplasia, anterolateral bowing of the tibia, and pseudoarthrosis are the most characteristic skeletal abnormalities and are part of the revised neurofibromatosis 1 diagnostic criteria (63). Sphenoid wing dysplasia occurs in approximately 5% to 12% of children with neurofibromatosis 1, and over 50% of cases of sphenoid wing dysplasia are associated with neurofibromatosis 1. It is congenital, although it is generally clinically apparent post-birth, but before the age of 2 years. The partial or complete absence of the greater wing of the sphenoid is associated with a prolapse of the temporal lobe in the orbital cavity, resulting in progressive facial asymmetry, proptosis, pulsating exophthalmos, restriction of extraocular movement, conjunctival inflammation, and pressure on the optic nerve with risk of blindness (25). Of those patients with sphenoid wing dysplasia, about 50% will develop ipsilateral temporal-orbital plexiform neurofibroma (50). Long bone dysplasia typically presents at birth or within the first months of life. It usually involves the distal third of the tibia and fibula, and less commonly of the radius and ulna, and presents as bowing of the affected extremity. Plain radiographs reveal pencil-point tapering of the bone with anterior lateral bowing. Fracture is frequent and surgical correction difficult (110). About half of fractures occur before age 2, with weight bearing or with first attempts of walking. Impaired fracture healing is frequent, and when there is nonunion of bone fragments at the site of a long bone fracture, a false (“pseudo”) joint (“arthrosis”) forms, called pseudoarthrosis. Pseudoarthrosis occurs in 2% to 5% of patients with neurofibromatosis 1, and neurofibromatosis 1 accounts for 50% to 80% of all pseudoarthrosis cases.

Bony erosion and demineralization are often caused by pressure from adjacent plexiform neurofibromas (110). Nonossifying fibromas usually involve the femur, tibia, and humerus, are painful, and can lead to fracture. They occur mainly in late childhood and early teenage years. Surgical treatment is problematic, and intervention should be limited to supportive measures and treatment of fractures.

Scoliosis occurs in 10% to 30% of patients with neurofibromatosis 1 and is generally classified into dystrophic and nondystrophic based on the presence or absence of skeletal dysplasia on plain radiographs. Between 3 to 5 years of age, scoliosis is often dystrophic, severe, and rapidly progressive and requires surgical correction (110). During the teenage years, scoliosis is more often a self-limited idiopathic juvenile scoliosis and often treated with bracing. Scoliosis may also occur because of vertebral instability secondary to vertebral dysplasia or vertebral erosion from adjacent plexiform neurofibromas (110). Dystrophic scoliosis is characterized by short-segment, sharply angulated curve that usually involves four to six spinal segments, and dystrophic features such as vertebral scalloping or wedging, rib penciling, or spindling of the transverse process. Patients with three or more dysplastic features have an 85% risk of curve progression and should be aggressively managed. Importantly, about 75% of children aged less than 7 years will have a transformation from nondystrophic to dystrophic scoliosis (102).

Osteopenia or osteoporosis occur in about 50% of patients with neurofibromatosis 1 (94), and usually earlier than in the general population (71). The pathogenesis of these bony changes is not understood, but individuals with neurofibromatosis 1 may have lower than expected serum 25-hydroxyvitamin D concentrations, elevated serum parathyroid hormone levels, disorders of phosphorus and calcium metabolism, and evidence of increased bone resorption (55; 14). There is no consensus on the treatment of neurofibromatosis 1-related osteoporosis; calcium and vitamin D and bisphosphonates have all been tried (12; 94). Some authors recommend DEXA screening starting at the age of 40 years and repeat scans based on the degree of bone loss, along with calcium and vitamin D supplementation (71). A trial on the therapeutic role of vitamin D supplementation is ongoing (NCT01968590).

Short stature (defined by two standard deviations below the population mean) occurs in about 30% of patients with neurofibromatosis 1 and is not usually associated with hormonal dysfunction (110; 50). Growth charts made specifically for children with neurofibromatosis 1 are available.

Congenital thoracic deformities, such as pectus excavatum or carinatum, have also been reported in about 3% of patients with neurofibromatosis 1 (14).

Endocrine manifestations

Delayed puberty occurs in approximately 30% of adolescents with neurofibromatosis 1, whereas precocious puberty is seen in 3% of patients (14).

Oral manifestations

About 70% to 90% of patients with neurofibromatosis 1 have alterations in soft tissues, jaws, teeth, and salivary glands, such as oral mucosa or intraosseous neurofibromas, enlarged fungiform papillae of the tongue, hyposalivation, enlarged mandibular canal, mandibular and mental foramen, and alteration in craniofacial morphology, among others. It is important that physicians and dentists are aware of such manifestations so that preventive measures can be introduced and proper diagnosis and management performed (29).

Thoraco-pulmonary manifestations

About 10% to 20% of adult with neurofibromatosis 1 have pulmonary manifestations, which typically include bilateral basal reticulations, apical bullae and cysts, and pulmonary hypertension. Clinically, neurofibromatosis-associated diffuse lung disease (NF-DLD) appears in the third or fourth decade of life, and presents with nonspecific respiratory symptoms, including dyspnea on exertion, shortness of breath, chronic cough, or chest pain. A chest CT is the most reliable method for diagnosis.

Neurofibromatosis 1–related pulmonary hypertension (PH-NF1) has an incidence estimated to be 1 out of 1000, although it is probably underestimated and is characterized by a female predominance, a low DLCO, severe functional and hemodynamic impairment, and an overall poor prognosis. A specific neurofibromatosis 1-vasculopathy is believed to play a major role into the development of PH-NF1. Its low incidence, late onset, and female predominance suggest that a predisposition or a second hit might be necessary for the development of pulmonary vasculopathy (57).

The thorax and lungs can also be affected by the development of neurofibromas on the chest wall, kyphoscoliosis, rib deformity due to bone dysplasia or erosion by adjacent neurofibromas, posterior vertebral scalloping, intrathoracic neurogenic neoplasms, meningoceles, and interstitial parenchymal lesions, which are generally bilateral, symmetrical, and predominantly basal.

Up to 25% of patients with neurofibromatosis 1 have dural ectasia (a dilatation of the dural sac) at a median age of 36 years (range 18 to 64 years) (100; 103). Intrathoracic meningocele are saccular protrusion of dysplastic meninges into the thoracic cavity through a pathologically dilated intravertebral foramen or a bone defect in a thoracic vertebra, usually occurring in association with thoracic scoliosis. MRIs are usually diagnostic, showing meningoceles with the same signal intensity as the cerebrospinal fluid in all sequences. Most are indolent and do not require intervention. However, the more severe the dural ectasia, the greater the likelihood of a concurrent spinal deformity, and thus, some believe that patients with incidentally found moderate to severe dural ectasia should be offered increased surveillance for the development of scoliosis (100).

Neurofibromatosis 1 may also increase the sensitivity of the lungs to cigarette smoke, increasing the severity of neurofibromatosis-associated diffuse lung disease in smokers (05).

Neurologic manifestations

Cognitive and behavioral disorders. About 90% of children with neurofibromatosis 1 have IQ scores between the low and average range; IQ scores are 5 to 10 points lower than controls (54; 109). The incidence of intellectual disability (IQ < 70) is, however, only slightly higher than that of general population (4% to 8% vs. 2% to 3%) (50). Up to 80% of children with neurofibromatosis 1 experience cognitive and behavioral difficulties involving different domains, including language skills (verbal, reading, writing), visuospatial skills, fine and gross motor functions, executive functions, attention, behavior, emotion, and social skills (109). About 40% of children with neurofibromatosis 1 present specific learning disabilities, compared to 6% to 10% in the general population. In addition, close to 40% have attention-deficit/hyperactivity disorder, which can also impact overall scholastic performance. Neurofibromatosis 1 is indeed associated with reduced educational attainment (56). Studies also suggest a higher prevalence of autistic traits and autism spectrum disorder (109), as well as an increased risk of Alzheimer disease (58).

A systematic review of randomized controlled trials on the use of statins in neurofibromatosis 1 children reported no beneficial effect of statins in cognitive function and behavioral problems in this population (02). However, children with neurofibromatosis 1 and attention-deficit/hyperactivity disorder seem to benefit from methylphenidate treatment (67; 109). Although cognitive deficits have been strongly related to the presence of thalamic T2 hyperintensities (termed NF-associated bright spots) in brain MRI, more studies are needed to clarify this association (53; 109). No robust and reproductible link between the presence, number, or localization of these neurofibromatosis-associated bright spots and major cognitive deficits has not yet been established (11).

Psychopathology. Children and adolescents with neurofibromatosis 1 also have more anxiety symptoms, more sleep disturbances, a higher degree of loneliness than siblings, and an overall reduced quality of life. Suicidal ideation is also significantly higher in patients with neurofibromatosis 1 (45%) than in controls (10%). They could benefit from suicide assessment and interventions focused on social skills and emotional support (109; 13).

Epilepsy. Seizures are approximately twice as common in patients with neurofibromatosis 1 compared with the general population, with a prevalence of approximately 4% to 10%; however, they are more often focal and related to an underlying intracranial neoplasm or structural abnormalities, including hippocampal sclerosis and polymicrogyria (07; 82). Thus, new seizures should prompt repeat neuroimaging, even if previous imaging was normal. Epilepsy may be nonlesional in a significant proportion of patients with neurofibromatosis 1 and may be attributed to the existence of endogenous dysregulation of electrical brain activity (99). Management of patients with neurofibromatosis 1 with epilepsy is otherwise similar to epilepsy in the general population.

Macrocephaly. At least 50% of individuals with neurofibromatosis 1 have a head circumference at greater than the 98th percentile, caused by increased brain volume (megalencephaly), or, rarely, hydrocephalus due to cerebral aqueductal stenosis (54; 53). Up to 13% of patients with neurofibromatosis 1 will develop hydrocephalus (95). Macrocephaly does not correlate with cognition or clinical severity and is not associated with any intracranial or endocrinologic pathology (54; 110). Aqueductal stenosis occurs in 1% of patients with neurofibromatosis 1, usually in late childhood, and presents as insidious onset of headache, gross motor incoordination, and falling (110). It is best treated by third ventricle fenestration.

Headache. Triptans should be avoided in patients with known vessel disease such as moyamoya vasculopathy or renal artery stenosis (85).

Myopathy. Children with neurofibromatosis 1 are more likely to have reduced muscle force and power. Neurofibromatosis 1-related muscle weakness may manifest as fatigue, often reported as not being able to do as much activity as their peers, insisting on use of strollers/buggies for even short walking distances and tiring hands when writing. Muscle biopsies suggest an underlying pathophysiology that involves defects in lipid metabolism (27). A small study demonstrated that 12 weeks of L-carnitine supplementation increased strength and is safe and feasible in children with neurofibromatosis 1; a phase 3 trial should confirm the efficacy of treatment (113).

Small fiber neuropathy. In the absence of other causes for neuropathy, preliminary data revealed that up to one out of four of patients with neurofibromatosis 1 may have small fiber neuropathy, suggesting that this may be a manifestation of the disease (10). Enlarged spinal nerve roots are also a neuroradiological finding in neurofibromatosis 1 (26).

Pain. A survey of 255 adults with neurofibromatosis 1 extends previous research reporting that most individuals with neurofibromatosis 1 are dealing with significant pain and interference. Although this pain can be associated with neurofibromas, it is often not localized to a specific structural lesion (21). Further research is necessary to evaluate the relationship between pain severity and quality of life.

Vascular manifestations. The exact incidence of neurofibromatosis 1-vasculopathy is unknown but is estimated to affect up to 15% of patients with neurofibromatosis 1 (97; 91). The two most common vascular changes associated with neurofibromatosis 1 are hypertension and vascular dysplasia.

Hypertension. Up to 20% of patients with neurofibromatosis 1 may develop hypertension at any age (14; 91). Most cases of neurofibromatosis 1-associated hypertension are primary (essential) among adult, but secondary causes include renal vascular dysplasia (renal artery stenosis), pheochromocytoma, and coarctation of the aorta (55). Renal artery stenosis occurs in approximately 1% of patients with neurofibromatosis 1 (110) and in up to 40% of patients with neurofibromatosis 1 with vasculopathy, and it is the leading cause of pediatric hypertension (91). Thus, any patient with neurofibromatosis 1 and hypertension should be evaluated for renovascular causes and pheochromocytoma.

Vascular dysplasia. Neurofibromatosis 1-associated vascular dysplasia more commonly affects arteries, is usually multifocal and bilateral, and can cause stenosis, occlusion, aneurysm, pseudoaneurysm, rupture, or arteriovenous fistula formation (110; 55). The neurofibromatosis 1 protein, neurofibromin, is robustly expressed in endothelial cell vessels and smooth muscle cells. Dysplasia of the intracranial vessels affects about 7% to 19% of children with neurofibromatosis 1. It may present as bilateral stenosis/occlusions of proximal vessels of the anterior circulation and subsequently induce the formation of prominent peristenotic collateral circulation appearing as “puff of smoke” (moyamoya) on cerebral angiography, called moyamoya syndrome (55; 91). Children with neurofibromatosis 1 are at increased risk of developing moyamoya after cranial irradiation (55), and radiotherapy is avoided as much as possible in patients with neurofibromatosis 1. Moyamoya syndrome in children can manifest as ischemic stroke in about 60% of affected individuals, mainly of a watershed pattern, whereas vascular dysplasia in adults typically causes hemorrhage and arterial dissection (118; 07). Headache, seizures, and transient ischemic attacks are other moyamoya manifestations. Adults with neurofibromatosis 1 have a 20% odds of ischemic stroke and almost 2-fold higher odds of hemorrhagic stroke (64).

Dysplasia of the aorta and abdominal visceral arteries affects about 12% of patients with neurofibromatosis 1. Middle aortic syndrome can arise in the presence of neurofibromatosis 1 vasculopathy when there is narrowing of the abdominal aorta and associated stenosis of renal (63%) and mesenteric (33%) arteries. Vasculopathic changes to intra-abdominal arteries can result in abdominal pain, organ dysfunction, bowel ischemia, and intra-abdominal bleeding (91).

Prognosis and complications

	• Life expectancy in neurofibromatosis 1 may be reduced by 15 to 25 years.
	• Patients with neurofibromatosis 1 have an overall incidence of cancer that is 3% higher than the general population. They carry a 2.7-fold increased risk of various cancers, and the cumulative risk of malignancy is 20% by 50 years of age.
	• Women with neurofibromatosis 1 aged 30 to 50 years old have a 5-fold increased risk of breast cancer and should access extra breast screening. Neurofibromatosis 1–associated breast cancers seem to have a poorer outcome compared to non-neurofibromatosis 1 breast cancers.
	• Up to 20% of patients with neurofibromatosis 1 with optic pathway gliomas will develop another glioma.
	• Patients with neurofibromatosis 1 have a 10- to 50-fold greater risk of developing high-grade glioma than the rest of the population.
	• Brainstem glioma occurs in less than 10% of neurofibromatosis patients, with a majority being asymptomatic with a benign course and no need for treatment.
	• Catecholamine-secreting tumors are found in less than 5% of patients with neurofibromatosis, of which about 50% are symptomatic.

Life expectancy in neurofibromatosis 1 is reduced by 15 to 25 years, with early mortality attributed to malignancy and vascular disease, discussed below (32; 14).

Tumors. Neurofibromatosis 1 is a common cancer predisposition syndrome in which affected children and adults develop benign and malignant nervous system tumors, as well as unusual systemic tumors such as sarcomas, stromal tumors, neuroendocrine tumors, and hematopoietic tumors (Table 4) (70). Of all the characteristic features of neurofibromatosis 1, the presence of neoplasms contributes the most to the morbidity and mortality experienced by this population (04), and especially to the mortality in younger age groups (less than 40 years). Patients with neurofibromatosis 1 are 4 times more likely to develop a malignancy as compared to the general population (14). They carry a 2.7-fold increased risk of various cancers, and the cumulative risk of malignancy is 20% by age 50 (32).

The most common neurofibromatosis 1-associated tumors are neurofibromas and optic pathway gliomas, seen in about 90% and 15% of patients, respectively. The most common neurofibromatosis 1-associated malignant tumor is malignant peripheral nerve sheath tumors, seen in about 10% of patients (55).

Notably, both neurofibromas and optic pathway gliomas are associated with an increased risk of additional tumor; up to 10% plexiform neurofibromas will transform into malignant peripheral nerve sheath tumors, and up to 20% of patients with optic pathway glioma will develop another glioma (37). Neurofibromas and optic pathway glioma are part of the diagnostic criteria and are, hence, discussed in the Presentation and course section.

Central and peripheral nervous system tumors. Among neurofibromatosis 1-associated CNS tumors, over 60% are optic pathway gliomas, 18% are brainstem gliomas (73), and the remaining are glioblastomas and, more rarely, SEGA-like astrocytomas, glioneural tumors, ependymomas, meningiomas, and medulloblastomas (88; 69; 82). Additional CNS tumors have been found in at least 20% of patients with optic pathway glioma, and substantially more in those previously treated with radiotherapy, which is in part why radiotherapy is no longer recommended for optic pathway gliomas in people with neurofibromatosis 1 (55).

The majority of neurofibromatosis 1-associated CNS tumors are gliomas. Most pediatric gliomas are low-grade gliomas, commonly involving the optic pathway (85%) or the brainstem, basal ganglia, or cerebellum, and they occur more frequently in the first 10 years of life. By contrast, high-grade gliomas occur in about 1% of patients with neurofibromatosis 1, more frequently in young adults (mean age of 38 years, which is much younger than the mean age for patients with sporadic glioblastoma) (37; 31; 69; 82). Patients with neurofibromatosis 1 have a 10- to 50-fold greater risk than the general population to develop such malignant tumors (18; 49). For patients who develop a high-grade glioma, genetic investigation for constitutional mismatch repair deficiency syndrome (CMMRD) is recommended, as patients with CMMRD are susceptible to high-grade glioma and show phenotypic overlap with neurofibromatosis 1 syndrome (82).

Neurofibromatosis 1-associated gliomas have been found to have distinct genetic signature; low-grade gliomas seem to exhibit fewer mutations that are over-represented in genes of the MAPK pathway, whereas high-grade gliomas have higher mutation burden and frequent mutations of ATRX, typically co-occurring with alterations of TP53 and CDKN2A, with no IDH mutations, regardless of grade, or H3 mutations (69). The molecular alterations responsible for anaplasia in pilocytic astrocytoma (anaplastic astrocytoma with piloid features) have been described (93).

Brainstem gliomas. Brainstem gliomas occur in small minority (less than 10%) of patients with neurofibromatosis 1 (28). They usually occur later than optic pathway gliomas (mean age at diagnosis, 7 vs. 4 years) (73). The largest series on 133 neurofibromatosis 1-associated brainstem gliomas showed that most of these tumors occurred in the midbrain and medulla (over 60%), the majority were asymptomatic (over 50%), the course was usually benign with no progression (over 85%), and only 30% required tumor-directed treatment, mainly due to symptoms or radiological progression. No deaths were reported among patients who were untreated (73). Of the brainstem gliomas that were biopsied in this study, histologies included pilocytic astrocytoma and WHO grade 2 gliomas; this is in contrast to sporadic brainstem gliomas where pontine involvement and higher grade (consisting mostly of midline gliomas with histone mutations) are most common (73).

Malignant peripheral nerve sheath tumors. Malignant peripheral nerve sheath tumors are aggressive soft tissue sarcomas thought to derive from Schwann cells. Up to 50% of all malignant peripheral nerve sheath tumors are associated with neurofibromatosis 1. Neurofibromatosis 1-associated malignant peripheral nerve sheath tumors usually arise from benign precursors (plexiform neurofibromas or large intraneural [nodular] neurofibromas) in which additional somatic alterations occurred, such as loss of cell cycle regulators (p16/CDKN2A) and polycomb repressor complex components EED and SUZ12 (77). About 10% of theses intraneural (nodular) and plexiform neurofibromas will eventually transform into malignant peripheral nerve sheath tumors (07). Patients with neurofibromatosis 1 have a lifetime risk for development of malignant peripheral nerve sheath tumors of approximately 10% (8% to 16%) (18; 77), and malignant peripheral nerve sheath tumors represent the leading cause of mortality in adults with neurofibromatosis 1 (88). Neurofibromatosis 1-associated malignant peripheral nerve sheath tumors affect younger patients (mean age 25 to 35 years vs. 40 to 45 years) and have poorer prognosis than sporadic malignant peripheral nerve sheath tumors (70). They most commonly involve brachial plexus, paraspinal region and buttock, and sciatic nerve, and appear to be more frequent than expected in the radiotherapy field of neurofibromatosis 1-associated optic pathway gliomas (70). Negative prognostic factors include truncal (axial) tumor location, size greater than or equal to 5 cm, high-grade (WHO grade 3) designation, and metastasis (70). The 5-year overall survival is approximately 20% to 50%, and the outcome is particularly dismal in those with unresectable or metastatic disease (77).

Embryonal rhabdomyosarcoma. Embryonal rhabdomyosarcoma occurs in less than 1% of children with neurofibromatosis 1, usually before age 5, with the urogenital system being the most frequent site involved. The prognosis and overall survival are equivalent to that of non-neurofibromatosis 1 embryonal rhabdomyosarcoma (37). There are insufficient data to recommend any routine screening.

Juvenile myelomonocytic leukemia. Juvenile myelomonocytic leukemia is a rare, aggressive myeloproliferative/myelodysplastic disorder of infancy and childhood causing infiltration of the peripheral blood, bone marrow, and viscera by abnormal myelomonocytic cells. About 90% of patients with juvenile myelomonocytic leukemia have somatic or germline mutations of genes within the RAS/MAPK signaling pathway, and 10% to 15% have neurofibromatosis 1 (24). Although juvenile myelomonocytic leukemia occurs in only 1 in 300 children with neurofibromatosis 1 (37), the risk is about 350 times greater than in children without neurofibromatosis 1 (24). The median age at presentation is 2 years (range, 0.1 to 11.4) and there is a male predominance (over 2:1) (24). Juvenile myelomonocytic leukemia can present as an acute illness with fever and signs of upper respiratory infection, or, more commonly, with indolent symptoms such as malaise, pallor, or bleeding. Signs of rash, pallor, lymphadenopathy, or hepatosplenomegaly should be carefully sought on examination, as they are present in over 30%, 60%, 75%, and 95% of cases, respectively (24). Complete blood count and peripheral blood smear are the first step in establishing a diagnosis (Table 4). Allogeneic hematopoietic cell transplantation is the only curative therapy and is recommended for all neurofibromatosis 1-associated juvenile myelomonocytic leukemia. Median survival of children who do not undergo transplantation is as short as 10 to 12 months, whereas 5-year overall survival is about 60% in transplanted patients (24).

Table 4. WHO Diagnostic Criteria for Juvenile Myelomonocytic Leukemia in Patients with Neurofibromatosis 1

All mandatory:

(1) Splenomegaly (2) Peripheral blood monocyte count ≥ 1 × 109/L (3) Blast percentage in peripheral blood and bone marrow < 20%

(08)

Early-onset breast cancer. Women with neurofibromatosis 1 ages 30 to 50 years have a 5-fold increased breast cancer risk and should access extra breast screening according to guidelines for moderate (20%) lifetime risk or high risk if there is additional family history of breast cancer (37). A survey conducted in several neurofibromatosis clinics in the United States has demonstrated a 17% lifetime risk of breast cancer in women affected with neurofibromatosis 1, and the cumulative risk at age 50 is estimated to be 9%. Neurofibromatosis 1-associated breast cancers seem to have a poorer outcome compared to non-neurofibromatosis 1 breast cancers, likely due to more aggressive tumor phenotypes (increased in triple-negative [ER, PR, HER2] and HER2-positive tumor subtypes) and later presentation (51).

Gastrointestinal stromal tumors. Patients with neurofibromatosis 1 are also at an increased risk (about 45-fold increased risk) of developing soft tissue sarcomas arising within the stromal compartment of the gastrointestinal tract, which are termed gastrointestinal stromal tumors (GIST) (16). These tumors are the most common gastrointestinal tumors reported in the neurofibromatosis 1 population and occur in around 2% of children and 6% of adults with neurofibromatosis 1. They occur younger than sporadic gastrointestinal stromal tumors (mean age 49 vs. 56), most frequently involve the small intestine (over 70%, vs. stomach), are multiple, are more often asymptomatic (53% vs. 19% of sporadic GIST), have a more indolent course, and have a different molecular pathology than non-neurofibromatosis 1 gastrointestinal stromal tumors (37; 43; 33). These tumors do not harbor the mutations in KIT, PDGFRA, and BRAF that are typically associated with sporadic gastrointestinal stromal tumors and are, therefore, poorly responsive to the tyrosine kinase inhibitors, such as imatinib, sunitinib, or regorafenib (14; 16).

Gastrointestinal neuroendocrine neoplasms. Gastrointestinal neuroendocrine neoplasms are more common in neurofibromatosis 1 individuals than in the general population. They have a predilection for the peri-ampullary duodenum or near the ampulla of Vater and are well-differentiated, with favorable tumor biology. Approximately 40% are somatostatinomas but typically do not present with the classic symptoms of diarrhea, diabetes, dyspepsia, and cholelithiasis. Instead, they may be clinically silent or present with obstructive jaundice, duodenal obstruction, pancreatitis, or cholangitis. The diagnosis relies on CT, endoscopic ultrasound, and serum chromogranin A and urinary 5-HIAA. Management is similar to non-neurofibromatosis 1 neuroendocrine neoplasm (33).

Catecholamine-secreting tumors. Catecholamine-secreting tumors arise from chromaffin cells of either the adrenal medulla (referred to as "pheochromocytomas"), or the sympathetic ganglia (referred to as "catecholamine-secreting paragangliomas" or “extra-adrenal pheochromocytomas”); however, the term “pheochromocytoma” is often used to refer to both. Approximately 30% of patients with catecholamine-secreting tumors have the disease as part of a familial disorder, such as neurofibromatosis 1, and approximately 7% (0.1%-13%) of patients with neurofibromatosis 1 develop catecholamine-secreting tumors (14). In these patients with neurofibromatosis 1, the tumors are more likely to present at a younger age and to be a solitary benign adrenal pheochromocytoma (115). About 10% are bilateral adrenal pheochromocytoma, 10% are extra-adrenal paraganglioma, and 10% are malignant, but 95% are within the abdomen and the pelvis (115). The majority are asymptomatic (80%) and nonsecreting (50%) (14). Patients with symptoms may present with paroxysmal headaches (90%), sweating (70%), and tachycardia in association with hypertension; only 15% are normotensive. Given that most patients are asymptomatic, some authors argue that screening for pheochromocytoma should be undertaken in all patients with neurofibromatosis 1 starting at 40 years of age (14). The diagnosis of pheochromocytoma is based on biochemical confirmation of catecholamine hypersecretion (by measurements of 24-hour urinary metanephrines and catecholamines and plasma-free metanephrines), followed by identifying the tumor with imaging studies. On MRI, pheochromocytoma/paraganglioma appears as a T2/FLAIR hyperintense mass with cystic and hemorrhagic changes, increased mass vascularity, and delay in contrast washout (< 50% after 10 minutes). Surgical resection results in cure in about 85% of patients; 15% of tumors recur and nearly half of these are malignant (06). Age, familial disease, and tumor site and size are independent predictors of recurrence. The risk of recurrence was 3.4-fold higher in patients with familial disease than in those with sporadic tumors (06). The possibility of concomitant pheochromocytoma in hypertensive patients with neurofibromatosis 1 who have surgery planned for other indication should be considered, and where necessary, preoperative evaluation with urinary catecholamines should be undertaken (33).

Glomus tumors. Up to 5% of patients with neurofibromatosis 1 are estimated to have a glomus tumor (89). Glomus tumors are small, benign but painful tumors that originate from the glomus body, a highly innervated thermoregulatory shunt concentrated in the fingers and toes (19). Glomus tumors in the fingers or toes are distinct from adrenal and extra-adrenal paragangliomas, also called ‘‘glomus tumors.” Affected individuals present with a triad of severe paroxysmal pain, cold intolerance, and localized tenderness under the nail bed of the fingers and toes. Glomus tumors are important to recognize because the pain is readily relieved by surgical removal of the tumor.

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 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, and optic disc pallor on the left greater than on the right. His general examination was notable for eight 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 extending anteriorly into the proximal portions of both optic nerves and posteriorly into the proximal optic tracts. This had the typical appearance of an optic pathway glioma, and he was diagnosed with neurofibromatosis 1 on the basis of this tumor and his six café-au-lait spots greater than 5 mm in diameter. The boy was referred to a neurooncology multidisciplinary team. Clinical examination of his parents revealed that his mother had six café-au-lait spots greater than 15 mm in diameter and Lisch nodules, and she was also newly diagnosed with neurofibromatosis 1. The family was evaluated by a geneticist, who underwent genetic testing of the mother and her two children, confirming the presence of a NF1 germline mutation in the mother and the boy, but not in the other child. Genetic counseling was also performed at that time.

Because of the progressive visual symptoms, the boy was treated with chemotherapy consisting of carboplatin and vincristine over 1.5 years during which the tumor first decreased in size by 25% and then stabilized. His vision improved to 20/20 in the right eye and to 20/200 in the left. The tumor remained stable until the boy was 8 years of age when it again increased in size radiographically, but with no associated visual changes including color vision and comprehensive peripheral visual fields. The neurooncology tumor board decided to monitor the tumor every 3 to 6 months with MRI and ophthalmology evaluations, and the tumor stabilized on the following scans along with his visual acuity. He continued to have yearly ophthalmological evaluations until he was 20 years old.

The boy initially had normal motor and cognitive milestones, but he did show some difficulty with reading skills after entering school. He was diagnosed with a mild learning disability for which he received tutoring during his elementary school years. He developed several subcutaneous neurofibromas during adolescence that did not -required treatment. At 18-years-old, a whole-body MRI revealed one small left paraspinal plexiform neurofibroma, and the patient was instructed on the signs of malignant peripheral nerve sheath tumors. Upon transition to adult care, the natural history and genetics of neurofibromatosis 1 was reviewed, along with the importance of yearly follow-up. At 35 years of age, his tumor had remained stable, and he had developed no further complications associated with neurofibromatosis 1.

Biological basis

Etiology and pathogenesis

	• Neurofibromatosis 1 is a common autosomal dominant neurocutaneous disorder caused by germline mutations in the NF1 gene at chromosome 17, which encodes the protein neurofibromin. Penetrance is complete, but expression is highly variable and age dependent.
	• A mutation in one germline allele is sufficient to result in the clinical syndrome of neurofibromatosis 1. However, tumor formation appears to require the somatic loss of function in the second NF1 allele, at least in the tumor cell of origin.
	• Mosaic forms of neurofibromatosis 1 (MNF1 or segmental NF1) are caused by somatic mosaicism due to a postzygotic mutation in the NF1 gene and are characterized by neurofibromatosis 1 manifestations limited to one or multiple body segments (localized or generalized mosaic forms of neurofibromatosis 1). Thirty percent have neurofibromatosis 1 complications, and 6% have offspring with complete neurofibromatosis 1.
	• About 5% to 10% of patients with neurofibromatosis 1 have the neurofibromatosis 1 microdeletion syndrome (or “large deletion phenotype”), which causes a more severe phenotype.

Neurofibromatosis 1 is a neurocutaneous cancer predisposition syndrome due to mutations in the NF1 gene located at chromosome 17q11.2. The NF1 gene encodes a tumor suppressor protein called neurofibromin, a RAS GTPase-activating protein, which promotes the conversion of active RAS-GTP to inactive RAS-GDP. The majority of NF1 mutations result in a loss of function of neurofibromin, hence, activating the RAS pathways, which in turn initiate a cascade of downstream signaling pathways, including the MAPK and RAS/P13K/AKT/mTOR pathways. Activation of these pathways has a variety of cellular effects but generally leads to increased cellular proliferation, and results in an increased risk of benign and malignant neoplasms. Neurofibromatosis 1 is, thus, considered a RASopathy. Neurofibromin is expressed in most tissues, principally in the central (oligodendrocytes and neurons) and peripheral nervous system (Schwann cells) and in the adrenal glands (70).

Genetics. More than 1400 different mutations have been observed in patients with neurofibromatosis 1 (49; 17). Half of individuals with NF1 have inherited their mutation in an autosomal dominant fashion from an affected parent, and half have sporadic (de novo) mutation, with no family history of neurofibromatosis 1. Penetrance of the disease is complete, and nearly all individuals carrying the mutation will manifest the disorder by 8 years of age (34). However, its expression is highly variable, even among affected individuals within the same family sharing the same germline mutation.

Only few genotype-phenotype correlations have been clearly established to date. About 5% to 10% of patients with neurofibromatosis 1 have the neurofibromatosis 1 microdeletion syndrome (or “large deletion phenotype”), which is caused by large deletions including the entire NF1 gene. Patients with neurofibromatosis 1 microdeletion often show a more severe phenotype, including facial dysmorphism, mental retardation, developmental delay, numerous neurofibromas, and increased risk of malignant peripheral nerve sheath tumors, but not of breast cancer. The increased risk of malignant peripheral nerve sheath tumors is apparently due to SUZ12 gene deletion contiguous to NF1 (70). Missense mutation of codons 844 to 848 is associated with optic pathway gliomas, superficial plexiform neurofibromas, symptomatic spinal neurofibromas, skeletal abnormalities, and a higher risk of malignancy (71). Missense mutations at codon Arg 1809 are associated with developmental delay, learning disability, pulmonic stenosis, Noonan-like features, no superficial plexiform neurofibromas or symptomatic optic pathway gliomas. A single amino acid deletion at position 2971 is associated with only cutaneous findings of neurofibromatosis 1 (71). A specific in-frame deletion in exon 17 of the NF1 gene is associated with the absence of cutaneous neurofibromas and clinically obvious plexiform neurofibromas (70). Splicing or missense mutations seem to be more commonly found in patients with a phenotype referred to as "spinal neurofibromatosis," which is associated with multiple bilateral paraspinal neurofibromas with few cutaneous manifestations (70). In terms of phenotype severity, patients with truncating/splicing mutations and large deletions seem to require more medical attention than those with missense mutations (59).

In contrast to the most commonly encountered germline form of neurofibromatosis 1 are also mosaic forms of neurofibromatosis 1 in which a postzygotic somatic mutation may give rise to neurofibromatosis 1 manifestations limited to one body segment (localized mosaic forms of neurofibromatosis 1, previously called segmental neurofibromatosis), or, less frequently, to generalized mosaic forms of neurofibromatosis 1, sometimes clinically indistinguishable from the germline neurofibromatosis 1 (07). The phenotype depends on the timing of and cell lines affected by the mosaic mutation. Although individuals with mosaic forms of neurofibromatosis 1 have generally milder phenotypes than individuals with complete neurofibromatosis 1, about 30% have complications associated with neurofibromatosis 1, and 6% have offspring with complete neurofibromatosis 1. As such, it is recommended for all individuals with suspected mosaic forms of neurofibromatosis 1 to undergo complete physical examination, genetic testing of blood and skin, counseling, and health surveillance (42).

Genetic profile. Germline mutation in the NF1 gene constitutes the first hit in the second-hit cancer theory. A mutation in one germline allele is sufficient to result in the clinical syndrome of neurofibromatosis 1. Homozygous germline mutations in the NF1 gene are embryonically lethal (61). However, tumor formation appears to require the somatic loss of function in the second NF1 allele, at least in the tumor cell of origin (eg, in Schwann cells for neurofibromas). Unlike other cancer predisposition syndromes, neurofibromatosis 1-associated tumors are most frequently histologically benign. Malignant transformation (eg, malignant peripheral nerve sheath tumors) is thought to occur with the additional genetic changes such as alteration or loss in TP53, RB1, CDKN2A, SUZ12, or PTEN (60; 88).

Epidemiology

• The incidence of neurofibromatosis 1 is approximately 1 in 2000 to 3000 individuals, whereas that of mosaic neurofibromatosis is approximately 1 in 30,000 to 40,000.

Neurofibromatosis 1 is among the most common autosomal dominant genetic disorders. The incidence is approximately 1 in 2000 to 3000 individuals, and the prevalence ranges from 1 in 4000 to 1 in 7000 (36; 14). There is no ethnic or racial predominance. The incidence of mosaic neurofibromatosis 1 is estimated to be 1 out of 40,000 but is likely underestimated (17). Approximately 50% are familial cases, with a median age at diagnosis of 5 years, and 50% are sporadic cases, with a median age at diagnosis of 9.5 years (36). The average life expectancy of individuals with neurofibromatosis 1 is reduced by about 15 to 25 years relative to the general population (14).

Prevention

	• Annual history and physical examination (height, weight, blood pressure, skin, and neurologic exams) are recommended for all patients with neurofibromatosis. Those with hypertension should be evaluated for renal artery stenosis and, if negative, for pheochromocytoma.
	• At a minimum, yearly ophthalmological assessments should be performed from diagnosis up to 8 years of age and every 1 to 2 years thereafter until the age of 20.
	• Routine MRI screening for optic pathway gliomas is no longer advised in asymptomatic individuals with neurofibromatosis 1. Brain MRI should only be obtained in the event of focal signs or increased head size of plexiform neurofibroma of the head.
	• Whole-body MRI can be utilized as a screening tool for internal tumor detection in the asymptomatic patient with neurofibromatosis 1 population at high-risk of malignant peripheral nerve sheath tumors and at transition from childhood to adulthood, and if there is a desire to assess the total body burden of internal plexiform neurofibroma to establish a long-term surveillance plan for a given patient.
	• Heightened malignant peripheral nerve sheath tumor surveillance is required in the presence of risk factors, such as whole NF1 gene deletion, family history of malignant peripheral nerve sheath tumor, prior radiation therapy, large nodular or plexiform neurofibroma burden, or atypical neurofibroma.
	• Women aged 30 to 50 should be advised on the need for annual screening, either with mammogram or breast MRI.

Longitudinal follow-up. Once definitive diagnosis of neurofibromatosis 1 is established, longitudinal care is aimed at early detection of complications through annual medical visits to a multidisciplinary clinic, especially in the pediatric population, and patient/family education. All visits should include neurologic, skin, and ophthalmologic evaluations, as well as blood-pressure monitoring, with additional focus on problems appropriate to the age (Table 2). In children, behavior and development should be evaluated carefully, and formal neuropsychiatric evaluation may be necessary if concerns arise. Patients with abnormalities of the CNS, skeletal system, or cardiovascular system should be referred to appropriate specialists for evaluation. Health supervision and management guidelines have been published by The United Kingdom Neurofibromatosis Association Clinical Advisory Board (38), The Genetics Committee of the American Academy of Pediatrics (50), and The French National Guidelines (14). Recommendations for tumor surveillance have also been published by the AACR Childhood Cancer Predisposition Workshop (37) (Table 6), and the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS) (23). Imaging studies other than those recommended in Table 6 are indicated only when patients are symptomatic (03; 23). After baseline imaging of a symptomatic lesion, the optimal interval for surveillance is not established due to lack of evidence (03). Orbital and periorbital plexiform neurofibromas require close observation with regular ophthalmological and MRI evaluations because of the risk of progression (75; 23).

Whole-body imaging (WB-MRI). A systematic review of the literature summarizes current practices for MRI evaluation of people with neurofibromatosis 1; it discusses the use of whole-body MRI (03). Whole-body MRI can be utilized as a screening tool for internal tumor detection and when combined with diffusion-weighted imaging with apparent diffusion coefficient mapping it can enable simultaneous tumor characterization. Apparent diffusion coefficient < 1.0 x 10-3 mm2/s and an average diameter of > 4.2 cm are useful cut-off values for diagnosis malignancy with 100% sensitivity and negative predicting value, thereby making the apparent diffusion coefficient value a valuable biomarker in the assessment of malignant peripheral nerve sheath tumors. Whole-body MRI typically requires a 75-minute time slot and can be performed with either 1.5- or 3-Tesla magnet systems. Although the optimal use, timing, or utility of a screening whole-body MRI are not known, the authors suggest that whole-body MRI is best used in the asymptomatic neurofibromatosis 1 patient population at high-risk of malignant peripheral nerve sheath tumors, and if there is a desire to assess the total body burden of internal plexiform neurofibroma to establish a long-term surveillance plan for a given patient. Both higher numbers of plexiform neurofibromas and larger whole-body tumor volume have been implicated as important risk factors for the development of malignant peripheral nerve sheath tumors. By detecting the pattern and distribution of neurofibromas, whole-body MRI can also be helpful in distinguishing a germline from a segmental or mosaic presentation (Ahlawat and Blakeley 2020). Whole-body MRI is also recommended at transition from childhood to adulthood to evaluate internal tumor burden in the most recent tumor management guidelines for individuals with neurofibromatosis 1 (23).

Table 5. Main Tumors in Patients with Neurofibromatosis Type 1

Neurofibromas (40% to 90%)
	•Cutaneous (dermal) neurofibroma • Plexiform neurofibroma (subcutaneous, visceral, spinal, or orbital neurofibromas)
Gliomas
	• Pilocytic astrocytoma (OPG) (15%) • Diffuse low-grade glioma (midline) • High-grade glioma (1%)
Sarcomas and stromal tumors
	• Malignant peripheral nerve sheath tumor (MPNST) (10%) • Embryonal rhabdomyosarcoma (< 1%) • Gastrointestinal stromal tumor (GIST) (2% to 6%)
Neuroendocrine/neuroectodermal tumors
	• Pheochromocytoma (7%) • Wilm tumor • Carcinoid tumor (< 1%) • Medullary thyroid carcinoma
Hematopoietic tumors
	• Juvenile chronic myeloid leukemia (1 out of 300) • Juvenile xanthogranuloma
Other tumors
	• Melanoma • Early-onset breast cancer • Glomus tumors (< 5%)
(70)

Table 6. Health Supervision and Cancer Surveillance for Patients with Neurofibromatosis 1*

For all patients with neurofibromatosis 1
	• Genetic testing of the NF1 gene with an RNA-based approach. Testing of the SPRED1 gene if pigmentary features only.
	• Annual history and physical examination with primary care physician (height, weight, blood pressure, skin, and neurologic exams).
	• Annual clinical evaluation by a neurofibromatosis 1 specialist for patients with a high-risk phenotype** and every 2 to 3 years for patients without a high-risk phenotype.
		- Patient with hypertension should be evaluated for renal artery stenosis and, if negative, for pheochromocytoma.
	• 6 to 12 monthly ophthalmological assessments from diagnosis up to 8 years, and every 1 to 2 years thereafter until 20 years old.
		- Each visit: objective and quantitate visual acuity, confrontation visual fields, pupillary reflex and fundus exam +/- optical coherence tomography.
		- One baseline assessment of color vision and comprehensive peripheral visual fields, usually by 5 and 8 years old, respectively.
		- If vision loss is detected, repeat test in 2 weeks. If vision loss persists, obtain a brain MRI.
		- If an optic pathway glioma is diagnosed, follow under a neurooncology multidisciplinary clinic with 3 to 6 months MRI.
		- If treatment is required for optic pathway glioma, radiotherapy is not recommended.
	• Obtain a brain MRI for any persistent visual changes, marked increase in head size, plexiform neurofibroma of the head, or seizure.
	• Appropriate anticipatory guidance at all age groups (review the natural history and genetics of neurofibromatosis 1, advise the parents to report any unusual or new symptoms, stress the need for regularly scheduled visits, including careful cutaneous, skeletal, and neurologic examinations, evaluation of blood pressure, and ophthalmologic evaluation. Recommend available resources for patients with neurofibromatosis 1).
Specific to each age group
Newborn (Birth to 1 month)
	• Physical examination (café-au-lait spots, plexiform neurofibroma).
	• Physical examination of parents including slit-lamp examination for Lisch nodules.
		- If a parent if affected, all of the children must be examined.
		- Affected parents need to understand that there is a 50% risk of neurofibromatosis 1 for each pregnancy.
Infancy (1 month to 1 year)
	• History (neurodevelopment, symptoms of hydrocephalus).
	• Physical examination (head circumference, appropriate growth charts, proptosis, skeletal abnormalities [spine, long bone bowing, limb asymmetry]).
Early childhood (1 to 5 years)
	• History (neurodevelopment, language, motor skills, vision, Sx of juvenile myelomonocytic leukemia [fever, infection, rash, bleeding, fatigue]).
	• Physical examination (neurofibromas, skinfold freckling +/- medical photograph, vision, juvenile myelomonocytic leukemia [lymphadenopathy, pallor, rash, hepatosplenomegaly]).
Late childhood (5 to 13 years)
	• History (signs of learning difficulties, speech problems, attention-deficit/hyperactivity disorder, socialization, and self-esteem).
	• Physical examination (neurofibromas causing disfigurement, signs of puberty).
	• Obtain a consultation with a specialist if surgery for neurofibroma is desired to improve appearance or function.
	• If sexual precocity is present, evaluate for optic/hypothalamic glioma.
Adolescents (13 to 21 years)
	• Physical examination (pubertal development, plexiform neurofibroma).
	• Whole-body MRI (between 16 to 20 years).
	• Genetic counseling (discuss inheritance of neurofibromatosis 1, impact of puberty and oral contraceptives on neurofibromatosis 1, and risk for pregnancy).
	• Counseling on malignant peripheral nerve sheath tumor risk and symptoms.
Adults
	• History (symptoms of malignancy, including malignant peripheral nerve sheath tumors, symptoms of glomus tumors).
	• Physical examination (blood pressure, high-grade glioma, glomus tumor, malignant peripheral nerve sheath tumor, pheochromocytoma).
	• Counseling on early-onset breast cancer risk and need for yearly MRI from 30- to 50-years-old.
	• Prenatal counseling (explain the mechanism for occurrence of neurofibromatosis 1 in the fetus and the risk of recurrence, review the clinical manifestations, variability, progressive nature, and prognosis of the disorder; review the various forms of treatment and intervention currently available, including their efficacy, complications, and adverse effects; discuss the options available to the family for management and rearing of the child after in utero diagnosis [including continuation of the pregnancy or its termination], and after delivery, consider referral to a clinical geneticist for a more in-depth discussion, inform the family that there are specialty neurofibromatosis clinics that are available for guidance, therapy, and consultation).
MRI: magnetic resonance imaging; OCT: optical coherence tomography; OPG: optic pathway glioma; JMML: juvenile myelomonocytic leukemia; MPNST: malignant peripheral nerve sheath tumor *Adapted from the health supervision and management guidelines published by The United Kingdom Neurofibromatosis Association Clinical Advisory Board (38), The Genetics Committee of the American Academy of Pediatrics (50), and The French National Guidelines (14). The recommendations for tumor surveillance have been published by the AACR Childhood Cancer Predisposition Workshop (37), as well as from the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS) (23). **High-risk neurofibromatosis 1 phenotype are defined as patients with many subcutaneous neurofibromas and the presence of at least one internal neurofibroma because of its strong association with malignant peripheral nerve sheath tumor (14).

Genetic counseling. Genetic counseling is a critical part of the management of patients and their families. When neurofibromatosis 1 is suspected in a child, both parents should have medical histories, physical examinations, and ophthalmological examinations (including slit lamp examination) performed with particular attention to neurofibromatosis 1 features. Diagnosis of neurofibromatosis 1 in a parent may permit unequivocal diagnosis of neurofibromatosis 1 in a child, is essential for genetic counseling, and has important medical implications for the affected parent. Counseling entails verifying that the diagnosis is correct, informing the patient and family about the risk for the various potential complications, identifying recurrence risks, and providing emotional support. The unpredictability of the potential complications makes such counseling especially difficult with this disease. Because neurofibromatosis 1 is an autosomal dominant disease, the risk for each of an affected patient’s offspring having the disease is 50%.

Optic pathway glioma surveillance. Recommended surveillance for optic pathway glioma includes annual screening for endocrine abnormalities, with accurate growth charts, as well as 6-to-12-month ophthalmological assessments up to 8 years, and every one to 2 years thereafter until 20 years of age (Table 6), or for 10 to 25 years after initial diagnosis (71). Ophthalmologic assessment should include objective and quantitative visual acuity, confrontation visual fields, pupillary reflex, and fundus exam. Where available, optical coherence tomography should be added to every visit as an objective measure of axonal integrity/axonal loss and thickness of retinal nerve fiber layers (37). Initial studies indicate that retinal nerve fiber layers thickness and vision are associated (18). One baseline assessment of color vision and comprehensive peripheral visual fields should be undertaken when the child is mature enough to cope with the test, usually by 5 and 8 years old, respectively. If vision loss is detected (two lines worse than normal), and other causes excluded, a repeated test should be obtained in 2 weeks, and if vision loss persist, an MRI should be obtained. Thus, routine MRI screening for optic pathway glioma is no longer advised in asymptomatic individuals with neurofibromatosis 1. Acceptable normal visual acuities by age are 20/40 or better at age three, 20/30 at age four, 20/24 at age five, and 20/20 at age six and older (68).

Malignant peripheral nerve sheath tumor surveillance. A whole-body MRI should be considered between 16 and 20 years of age to assess internal burden and determine adult follow-up regimen (37; 23). Heightened surveillance is required in the presence of risk factors such as whole NF1 gene deletion, family history of malignant peripheral nerve sheath tumor, prior radiation therapy, large nodular or plexiform neurofibromas burden, or atypical neurofibroma (49; 92). Rapid growth, change in consistency, or development of significant pain associated with known neurofibromas should prompt evaluation to exclude a malignant peripheral nerve sheath tumor. Volumetric MRI is the gold standard for measuring plexiform neurofibromas, and a 20% volume change is indicative of change in tumor size. On MRI, malignant peripheral nerve sheath tumors are typically associated with peripheral enhancement and edema, intratumoral cystic lesions, necrosis, and heterogeneous signal intensity (71). Most plexiform neurofibromas grow rapidly during early childhood, whereas significant growth in adults should raise concern for malignant transformation (77). Upon transition to adult care, patients should be counseled on the future risk of malignant peripheral nerve sheath tumors and the cardinal symptoms and signs (37).

Breast cancer surveillance. Women ages 30 to 50 should be advised on the increased risk of breast cancer and the need for annual screening, either with mammogram or breast MRI (37; 51; 23). The most recent version of the NCCN guidelines advises annual mammograms starting at age 30 and consideration of breast MRI with contrast from ages 30 to 50 in the neurofibromatosis 1 population, although some authors advocate for annual breast MRI given the neurofibromatosis 1 increased risk of second tumors in response to ionizing radiation and the decreased sensitivity of mammogram in younger women (51). After 50 years of age, breast cancer risk in women with neurofibromatosis 1 mutation becomes similar to that of the rest of the population. Therefore, breast MRI could be discontinued, whereas mammography can be performed at longer intervals. No data on the benefit of risk-reducing mastectomy are available; therefore, this procedure may be considered based on family history (87).

Differential diagnosis

The conditions that are most often mistaken for neurofibromatosis 1 are those harboring similar skin findings or subcutaneous tumors (Table 7). Most of the time these conditions can be distinguished from neurofibromatosis 1 by their clinical features, although genetic testing may be required in some.

Individuals with multiple café-au-lait spots may warrant further investigations to rule out neurofibromatosis 1, familial café-au-lait spots, RASopathies such as Legius or LEOPARD syndromes, McCune-Albright syndrome, constitutional mismatch repair syndrome, neurofibromatosis 2, or segmental neurofibromatosis 1 (49). Familial café-au-lait spots are characterized by café-au-lait spots in many generations without other neurofibromatosis 1 features. They are believed to be of autosomal dominant transmission, although not yet characterized at a molecular level. Legius syndrome is an autosomal dominant neurofibromatosis 1-like syndrome caused by germline mutation of the SPRED1 gene, leading to loss of RAS protein suppressor function (thus a RASopathy). Legius syndrome is also characterized by café-au-lait spots, freckles, macrocephaly or learning difficulties, but, contrary to neurofibromatosis 1, lack Lisch nodules, typical osseous lesions, peripheral and CNS tumors, and NF1 gene mutation. Of importance, about half of individuals with Legius syndrome fulfill the neurofibromatosis 1 diagnostic criteria based on their cutaneous findings (café-au-lait spots and freckles). In a systematic review of the literature on the prevalence of neurofibromatosis 1 among patients with isolated café-au-lait spots with or without freckles after genetic testing, approximately 65% had neurofibromatosis 1, 8% had Legius syndrome, and the remaining had no diagnosis (14). LEOPARD syndrome is a rare autosomal dominant condition characterized by lentigines (L) that can differentiated from neurofibromatosis 1 because of its associated EKG abnormalities (E), ocular hypertelorism (O), pulmonic stenosis (P), abnormalities of genitals (A), retarded growth (R), or sensorineural deafness (D). McCune-Albright syndrome is a sporadic disease associated with a large segmental café-au-lait spots of more irregular “coast of Maine” borders compared with neurofibromatosis 1 café-au-lait spots “coast of California” borders, along with polyostotic fibrous dysplasia and precocious puberty (72). The constitutional mismatch repair deficiency (CMMRD) is a rare autosomal recessive disorder caused by deletion of both copies of one of the four mismatch repair genes (MLK1, MSH2, MSH6, and PMS2) sharing CaLS, axillary freckling, or Lisch nodules with NF1, but characterized by different types of malignancies (117). Because at least half of all patients with constitutional mismatch repair deficiency fulfill at least one criterion of neurofibromatosis 1, and because those neurofibromatosis 1 signs may be present prior to malignancies onset, CMMRD should be included in the differential diagnosis of an otherwise healthy child suspected to have neurofibromatosis 1/Legius syndrome without a detectable underlying NF1/SPRED1 germline mutation, without neurofibromatosis 1 signs in parents, and with at least one additional feature, either in the family or the patient (Table 8) (104). Genetic investigation for constitutional mismatch repair deficiency syndrome is recommended in patients with neurofibromatosis 1 who develop high-grade glioma (82). About one third of neurofibromatosis type 2 patients will have CaLS, although it is readily distinguished from neurofibromatosis 1 by its highly prevalent vestibular schwannoma.

Differential diagnosis for individuals with subcutaneous masses (other than neurofibromas) include familial multiple lipomatosis and Proteus syndrome. Familial multiple lipomatosis is an autosomal dominant clinical condition characterized by numerous lipomas or consistency similar to nodular neurofibromas, but firmer than dermal neurofibromas. Proteus syndrome is characterized by hamartomatous overgrowth of multiple tissues that may resemble a plexiform neurofibroma, and it has a characteristic gyriform pattern on the soles of the feet.

Table 7. Main Differential Diagnoses of Neurofibromatosis 1

Conditions with café-au-lait spots or similar pigmented macules
	• Familial café-au-lait spots (SPRED1 mutations) • Legius syndrome (SPRED1 mutations) • LEOPARD syndrome (PTPN11 mutations) • McCune-Albright syndrome (GNAS mutations) • Constitutional mismatch repair syndrome (CMMRD) • NF2-related schwannomatosis • Neurofibromatosis 2 • Segmental neurofibromatosis 1 (NF1 somatic mutations [mosaicism]) • Neurocutaneous melanosis
Conditions with freckles
	• Legius syndrome (SPRED1 mutations) • LEOPARD syndrome (PTPN11 mutations) • Cowden syndrome • Peutz-Jeghers syndromes
Conditions with subcutaneous tumors
	• Familial multiple lipomatosis • Multiple endocrine neoplasia type 2B • Complex combined vascular malformations • Congenital fibromatosis (infantile myofibromatosis) • Steatocystoma multiplex
Conditions with localized overgrowth syndromes
	• Proteus syndrome • Klippel-Trenaunay-Weber syndrome
(38; 49)

Table 8. Selection Strategy for Constitutional Mismatch Repair Deficiency Counseling and Testing

Prerequisites
	• At least one diagnostic neurofibromatosis 1 feature, including two hyperpigmented CALM-like macules
	• No NF1 and SPRED1 gremlin mutations
	• No diagnostic neurofibromatosis 1 feature in both parents
In the family
	• Genetic diagnosis of Lynch syndrome in parental family
	• Consanguineous parents
	• Sibling with diagnostic neurofibromatosis 1 feature
	• Sibling with any childhood malignancy
	• First or second degree relative less than 60 years of age with one of the following carcinoma: gastric, small bowel, bile duct, gall bladder, pancreatic, colorectal, endometrial, ovarian
In the patient
	• Atypical CALM (irregular boarders or pigmentation)
	• Hypopigmented skin patched
	• Pilomatricoma
	• Genesis of the corpus callous
	• Nontherapy-induced cavernoma
	• Multiple developmental vascular abnormalities in separate brain regions
(104)

Diagnostic workup

	• Screening MRI, EEG, and x-rays are no longer routinely recommended unless specific issues arise.
	• American Association for Cancer Research recommended that every child who met one (or more) neurofibromatosis 1 clinical criterion undergo genetic testing for the NF1 gene with an RNA-based approach and testing for the SPRED1 gene if pigmentary features are the only signs. The genetic testing for neurofibromatosis 1 has a sensitivity of more than 95%.
	• All suspected malignant peripheral nerve sheath tumor should be evaluated by MRI with diffusion-weighted imaging, positron emission tomography with 18-fluorodeoxyglucose, and biopsy. Needle biopsies are at risk of undersampling the tumor, and an FDG-PET/MRI-guided approach to obtain multiple specimens from radiologically suspicious regions can enhance the accuracy of preoperative diagnosis.
	• The diagnosis of atypical neurofibromatous neoplasm of uncertain biological potential should prompt additional sampling, clinical correlation, and possibly expert pathology consultation.

Clinical diagnosis. For most patients with neurofibromatosis 1, the diagnosis is made on the presence of two characteristic clinical manifestations (Table 1). When these National Institutes of Health diagnostic criteria are used, misdiagnosis is unlikely unless the diagnosis is made based only on pigmentary criteria. In patients presenting with isolated pigmentary criteria, only up to about 65% have neurofibromatosis 1 (15; 37).

Investigations at diagnosis. The Committee on Genetics of the American Academy of Pediatrics has published diagnostic and health supervision guidelines for children with neurofibromatosis 1 (50) (Table 6). Screening MRI, EEG, and x-rays are no longer routinely recommended unless specific issues arise. Genetic counseling and screening with targeted testing of the NF1 mutation identified in the patient should be considered in first-degree relatives (32). No NF1 biomarkers have been validated to date (48).

Genetic testing. Advances in molecular techniques over the last 2 decades have led to the availability of genetic diagnosis for neurofibromatosis 1, with a sensitivity of more than 95%. Based on new knowledge that a variety of syndromes have overlapping features with neurofibromatosis 1 but have a very different clinical course, and on the emerging therapeutic benefits observed with targeted therapies to the RAS/MAPK pathway in children with neurofibromatosis 1, the American Association for Cancer Research published recommendations for cancer surveillance in pediatric patients with neurofibromatosis 1, and recommended that every child who met one (or more) neurofibromatosis 1 clinical criterion undergo genetic testing for the NF1 gene with an RNA-based approach, and testing for the SPRED1 gene if pigmentary features are the only signs (37). They also recommended that patients with negative testing to NF1 and SPRED1 be considered for a gene panel including GNAS, MLH1, MSH2, MSH6, NF2, PMS2, PTN11, and SOS1. If no mutation is detected, testing for NF1 mutations from melanocytes cultured from at least two pigmentary lesions may be considered to evaluate for mosaicism, especially in the absence of family history of neurofibromatosis 1 (37).

Neurofibromatosis-associated bright spots. Approximately 60% to 70% of children with neurofibromatosis 1 harbor well-circumscribed, nonenhancing, T2-hyperintensity lesions in the thalamus, basal ganglia, cerebellum, and brainstem on brain and spine MRI, which are called T2H or NF-associated bright spots or focal abnormal signal intensities (98). The term “unidentified bright objects (UBOs)” is discouraged. The presence of mass effect, parenchymal infiltration, contrast enhancement, or increasing size should warrant further investigation for an underlying brain tumor. Although the precise etiology of these bright spots remains unknown, they may represent myelin vacuolar or spongiotic changes (82). They most commonly disappear by late adolescence or early adulthood (07).

Investigations of suspected optic pathway glioma. When an optic pathway glioma is clinically suspected, brain MRI with and without contrast is the preferred imaging for diagnosis and characterization of extension relative to the hypothalamus, optic chiasm, infundibulum, and optic nerve (intraorbital, intracanalicular, intracranial portions). A diagnosis of optic pathway glioma can be made on the sole basis of a typical imaging appearance (47). Typical MRI characteristics include enlarged optic nerve with central T2/FLAIR hyperintensity with variable enhancement and tubular thickening of the optic nerve. Globular lesions extending into hypothalamus are more characteristic of non-neurofibromatosis 1 lesions. However, a biopsy is advised whenever presentation is atypical.

Investigations of suspected malignant peripheral nerve sheath tumors. All suspected lesions should be evaluated by MRI (for characterization of size, site, and extension), positron emission tomography with 18-fluorodeoxyglucose (FDG-PET) (for biological behavior and metastasis), and biopsy (with surgical resection when appropriate) (for characterization of grade).

Contrast-enhanced MRI alone has been shown to be a suboptimal imaging modality for diagnosis of potential neurofibromatosis 1-related malignant peripheral nerve sheath tumors (specificity of 18% to 82% and sensitivity of 18% to 94%), whereas FDG-PET/CT has been shown to be able to predict with good specificity (72% to 95%), excellent sensitivity (91% to 100%), and negative predictive value whether malignant transformation has occurred; thus, it has been helpful in distinguishing malignant peripheral nerve sheath tumors from benign plexiform or nodular neurofibromas.

In MRI, MPNSTs specific morphological properties include irregular shapes and margins, heterogeneity within tumor, peritumoral edema, low T1WI signal, and a strong T2WI signal. Diffusion-weighted MRI improves precision compared to morphological MRI in the differentiation of malignant and benign lesions in neurofibromatosis patients, especially when borderline glucose metabolism of tumors is observed in FDG-PET imaging (75). Benign plexiform neurofibromas demonstrate low FDG uptake, whereas MPNSTs depict moderate to high FDG accumulation.

The optimum time for measuring commonly standard uptake values (SUV), the amount of FDG uptake, in patients with symptomatic PNFs is 240 minutes after injection of FDG (19). Standard uptake values usually range between 1.0 to 3.99 in benign tumors and between 3.1 to 21.4 in malignant lesions. However, there is no ideal standard uptake value cutoff value yet determined, and there is an overlap between plexiform neurofibromas and MPNSTs for standard uptake values between 2.5 to 3.5. Therefore, symptomatic plexiform neurofibromas with standard uptake values greater than or equal to 3.5 should be excised, and lesions with standard uptake values 2.5 to 3.5 should have precise clinical evaluation (111; 20; 75).

Needle biopsies are at risk of undersampling the tumor, and an FDG-PET/MRI-guided approach to obtain multiple specimens from radiologically suspicious regions can enhance the accuracy of preoperative diagnosis (77). Histology and immunohistochemistry usually further classify the peripheral nerve sheath tumor as either benign or malignant (Table 8). For benign tumors such as neurofibroma with atypia alone, there are no definitive data on risk for progression to malignant peripheral nerve sheath tumor (77). Occasionally, when tumors have some but not all features of malignancy, they are classified in the “possible malignant precursors” category, which is now referred to as atypical neurofibromatous neoplasm of uncertain biological potential (ANNUBP) (Table 9). They represent a clinical situation rather than a distinct diagnostic entity, and the diagnosis of atypical neurofibromatous neoplasm of uncertain biological potential should prompt additional sampling, clinical correlation, and possibly expert pathology consultation, although there is a lack of evidence to support a unifying standardized workup for those borderline/atypical masses (77). Although there is no single immunohistochemical or genetic test defining malignancy status in atypical neurofibromatous neoplasm of uncertain biological potential, helpful biomarkers in highlighting the transformation of a neurofibroma into a malignant peripheral nerve sheath tumor include loss of S100/Sox10, CD34+, p16/CDKN2A, and H3K27me3, as well as TP53 positivity and Ki67 greater than 10% (92). CDKN2A loss characterizes early steps in the malignant transformation of neurofibromas (75). H3K27me3 staining loss is the result of somatic alteration in the polycomb repressor complex components EED and SUZ12 and occurs in 34% to 73% of high-grade malignant peripheral nerve sheath tumors, whereas it remains positive in neurofibromas, atypical neurofibromatous neoplasms of uncertain biological potential, and most low-grade malignant peripheral nerve sheath tumors (76; 61).

Table 9. Proposed Pathological Nomenclature for the Spectrum of Neurofibromatosis 1–Associated Nerve Sheath Tumors

Nonmalignant
	• Neurofibroma
		Immunohistochemistry S100/Sox10 positivity for Schwannian cell lineage markers, and CD34+ fribroblastic network
	• Plexiform neurofibroma
		Neurofibroma involving multiple nerve fascicles, delineated by EMA+ perineurial cells
	• Neurofibroma with atypia
		Atypia alone
	• Cellular neurofibroma
		Hypercellularity alone, mitotic index < 1/50 high power field
Possible malignant precursor
	• Atypical neurofibromatous neoplasm of uncertain biological potential*
		2/4 of: cytological atypia, hypercellularity, loss of neurofibroma architecture, mitotic index 1/50 but < 3/10 high power field
	• Malignant peripheral nerve sheath tumor, low-grade*
		Atypical neurofibromatous neoplasm of uncertain biological potential with mitotic index 3-9/10 high power field
*currently diagnosed inconsistently as atypical neurofibroma or low-grade malignant peripheral nerve sheath tumor, although the term low-grade malignant peripheral nerve sheath tumor should be discouraged IHC=immunohistochemistry; HPF=high power field; MPNST=malignant peripheral nerve sheath tumor (77; 92)

Management

	• Radiotherapy is generally avoided in neurofibromatosis 1–associated benign tumors and is not recommended for optic pathway gliomas.
	• There are currently no approved effective medical or pharmacological treatments for cutaneous and subcutaneous neurofibromas. Trials are underway to identify new therapies.
	• Surgery is the current mainstay of therapy for plexiform neurofibromas, although they can rarely be fully resected. The MEK1/2 inhibitor, selumetinib, is now FDA-approved for children 2 years of age and older with inoperable, symptomatic plexiform neurofibromas. Its use in children with symptomatic plexiform neurofibromas, but without significant morbidity; in children with asymptomatic plexiform neurofibromas; and in adults with plexiform neurofibromas with associated morbidity or growth is currently being studied.
	• When a malignant peripheral nerve sheath tumor is suspected, surgical resection should be performed, with the extent of resection dependent on the pathological risk classification. There is no consensus on the use of chemotherapy, and there are no prospective data on the effect of chemotherapy on survival. Radiation should be administered to large, high-grade, malignant peripheral nerve sheath tumors, usually in the postoperative setting.
	• Treatment of optic pathway gliomas is based on documented clinical progression and, less commonly, on radiographic progression. The current standard is carboplatin and vincristine. Ongoing chemotherapy trials include the use of lenalidomide, selumetinib, vinblastine ± bevacizumab, and pegylated interferon.

Once identified, specific complications of neurofibromatosis 1 should be treated on an individual basis. Below is a brief survey of the general approach to the management of some of the frequent complications. Malignant tumors are generally approached in the same way as in a non-neurofibromatosis 1 patient, with specific therapy dependent on the particular tumor type. However, radiotherapy is generally avoided in neurofibromatosis 1-associated benign tumors and not recommended for optic pathway gliomas (37).

There has been important progress in clinical trials for patients with neurofibromatosis 1 over the past decade, with more than 40 phase 2 trials (both completed and ongoing), although with less than 10 were phase 3. Majority of clinical trials have focused on plexiform neurofibromas, whereas other tumor types within neurofibromatosis 1 have been less commonly studied. Overlooked areas of study include quality of life, pain, itch, and cognitive and behavioral abnormalities (01).

Skeletal abnormalities. Early and aggressive surgery is the most effective management for neurofibromatosis 1-associated dystrophic scoliosis (44). As sphenoid wing dysplasia complicated by proptosis is a progressive condition, an early surgical intervention is suggested, although no clear guidelines exist (25). Surgical correction of long bone dysplastic fractures is generally difficult, and prophylactic bracing should be instituted as soon as the lesion is recognized, before weight bearing, and continued to skeletal maturity (110). For significant (> 2 cm) leg-length discrepancy, destruction of the growth plate (epiphysiodesis) may arrest abnormal growth of the affected limb, allowing equalization of the extremities.

Vasculopathy. Unfortunately, there is no established consensus regarding medical management of NF1-associated vasculopathy. Most patients with neurofibromatosis 1 with moyamoya are started on antiplatelet agents to reduce the risk of ischemic stroke. Revascularization surgery is standard of care for children with symptomatic moyamoya, with a risk of perioperative stroke of 4% to 10% (64).

Neurofibromas. Most neurofibromatosis 1 neurofibromas are asymptomatic and mainly cause cosmetic problems; however, some may require surgical management when they are excessively large or in locations where they cause pain and prominent cosmetic disfigurement. Rapidly enlarging subcutaneous neurofibromas may require surgical intervention to evaluate for possible malignancy. Cutaneous neurofibromas present a major clinical burden for patients, and the development of effective medical therapies has been identified as a priority for most adults with neurofibromatosis 1 (22). First-line treatments include surgical excision or CO2 laser ablation. Second-line treatments include radiofrequency ablation and electrodessication (14). There are currently no approved effective medical or pharmacological treatments for cutaneous and subcutaneous neurofibromas, though trials are underway to identify new therapies with the MEK1/2 inhibitors selumetinib (NCT02839720), topical NFX-179 at higher concentrations (NCT05005845), as well as with topical diphencyprone (NCT05438290). Of note, a double-blind randomized controlled trial investigating the gel NGX-179 was completed in 2021, and complete statistical analysis is still pending (89). Photodynamic therapy involves pretreatment of a skin lesion with a photosensitizing agent followed by light exposure and is being evaluated in a phase II trial (NCT02728388). Topical diclofenac following laser microporation or cutaneous neurofibromas did not result in significant improvement (NCT03090971) (83).

Plexiform neurofibromas. Intervention for plexiform neurofibromas is reserved for those that are symptomatic, cause cosmetic disfigurement, are a threat to function (such as to vision from lid-orbital plexiform neurofibroma), or are worrisome for malignant transformation. Surgery is the current mainstay of therapy; however, the plexiform neurofibromas can rarely be fully resected due to their infiltrative nature and their involvement of critical structures, resulting frequently in regrowth after surgery (18). Moreover, surgical intervention carries a high risk of life-threatening hemorrhage, especially in cases of facial location (75). Radiation therapy has not been widely used for plexiform neurofibromas because of concern about increasing the potential for malignant transformation.

Approved MEK inhibitors. Selumetinib, a MEK1/2 inhibitor, is approved in the United States, the European Union, and other countries for children 2 years of age and older with inoperable, symptomatic plexiform neurofibroma based on the SPRINT trial. This phase I/II clinical trial enrolled patients in two strata: stratum 1 for symptomatic plexiform neurofibroma and stratum 2 for asymptomatic plexiform neurofibroma with the potential for development of complication. A published long-term analysis of SPRINT confirmed partial response (20% or more volumetric reduction) in 68% of patients, with a median best tumor response of -27.2%, and improvement in patient-reported outcomes, in both stratum 1 and 2 (09; 46). Selumetinib is currently studied in intermittent dosing schedule (5 days/7) in children with inoperable plexiform neurofibromas (NCT03326288), and in adults with inoperable plexiform neurofibroma-associated morbidity or recent growth (NCT02407405). Importantly, this last phase II trial also enrolls adults with histology confirmed atypical plexiform neurofibromas and will be informative whether these tumors are responsive to single-agent MEK inhibitor (45). A systematic review and metaanalysis including five studies involving 126 neurofibromatosis 1 children treated with selumetinib for their inoperable plexiform neurofibromas reported over 73% of response rate with a pooled 92.5% disease control rate, durable radiologic improvement in over 80% of patients, and a tolerable side-effect profile and safety level (52).

Investigational MEK inhibitors. To date, at least three other MEK inhibitors have progressed to clinical trials in neurofibromatosis 1 and show promising signs of reducing tumor volume and improving symptoms: trametinib (NCT02124772; NCT03741101), mirdametinib (NCT03962543; NCT02096471), and binimetinib (NCT03231306). Trametinib in pediatric populations and mirdametinib in adults (NCT03962543) found that 46% (12 out of 26) and 50% of patients, respectively, exhibited a greater than 20% decrease in target plexiform neurofibroma volume. Binimetinib is evaluated in a phase II trial for children and adults with neurofibromatosis 1 plexiform neurofibromas (NCT03231306). Preliminary data for 20 adults reported that 65% achieved partial response (09).

Investigational multiple tyrosine kinase inhibitor. Cabozantinib, a multireceptor tyrosine kinase inhibitor, showed partial response in 8 of 19 patients (42%, aged 16 years and older) in a phase II study (NCT02101736) (40). This trial has been expanded to include a pediatric cohort (3 to 15 years).

Other ongoing phase I and II trials are testing VEGFR inhibitors (cediranib and sunitinib), an mTOR inhibitor (everolimus), other MEK inhibitors (PD-0325901), c-kit inhibitors (nilotinib and PLX3397), and more conventional cytotoxic chemotherapies (vinblastine/methotrexate) (18).

The farnesyl transferase inhibitor, tipifarnib; the mTOR inhibitors (sirolimus, everolimus); and the fibroblast inhibitor, pirfenidone, did not provide enough benefit to support their use (14).

Malignant peripheral nerve sheath tumors. Once a malignant peripheral nerve sheath tumor is suspected from clinical exam and imaging (for example, in case of a rapidly growing symptomatic plexiform neurofibroma with a SUV > 3.5 on PET-FDG), surgical resection should be performed, with extent of resection depending on the pathological risk classification (Table 8). Benign tumors (neurofibromas, plexiform neurofibromas) can be treated relatively conservatively and even excised with positive margins, as supported by one follow-up study (77). Atypical neurofibromatous neoplasm of uncertain biological potential (or atypical neurofibromas and low-grade malignant peripheral nerve sheath tumor) typically require less aggressive surgery compared with high-grade malignant peripheral nerve sheath tumor, which requires wide excision with negative margins for potential cure (77). In the latter, radical surgery is the only curative treatment to date, but rarely achieved or too disfiguring.

The quality of evidence regarding optimal treatment options for neurofibromatosis 1-associated malignant peripheral nerve sheath tumors is weak (108). There is no consensus on the use of chemotherapy for malignant peripheral nerve sheath tumor, and there are no prospective data on the effect of chemotherapy on survival. Doxorubicin alone or in combination with ifosfamide is most currently used. Radiation should be administered to large, high-grade malignant peripheral nerve sheath tumor, usually in the preoperative setting (92). Multiple negative phase 2 studies for malignant peripheral nerve sheath tumor have been published or completed, mainly in the setting of recurrent/unresectable disease. To date, there are no FDA-approved treatments available. Multiple clinical trials for malignant peripheral nerve sheath tumor treatment are currently underway, including one investigating sirolimus ans selumetinib (NCT03433183), the multi-kinase inhibitor PLX3397 in combination with rapamycin (NCT02584647), and the CDK4/6 inhibitor ribociclin (NCT03009201) (89).

Optic pathway glioma. Once an optic pathway glioma is diagnosed, the patient should be followed under a neurooncology multidisciplinary team to evaluate the need of treatment and should be monitored with 3- to 6-month MRIs (37). Management of neurofibromatosis 1-associated optic pathway glioma is somewhat controversial and must be individualized based on patient’s age, clinical presentation (visual deficits, hydrocephalus, diencephalic syndrome, etc.), tumor location (anterior vs. posterior optic pathway), and side effect profile of the treatment. Treatment of optic pathway glioma is based on documented clinical progression and less commonly on radiographic progression (increase in tumor size or in enhancement) because radiographic progression has not yet proven to be a good correlate for visual function and response to treatment (39; 105). Most clinicians reserve treatment for patients who have a decline in visual acuity or new visual field defect, whereas a modest amount of tumor increase can be tolerated if vision is stable (30). The goal of treatment is to prevent progression and preserve vision, but actual improvement of visual acuity is seen in up to one third of patients posttreatment (30). Options include conservative treatment with regular follow-up, chemotherapy, surgery, radiotherapy, targeted therapy, and clinical trial participation, although radiotherapy should be avoided (37; 105). They are briefly discussed below.

Conservative treatment. In contrast to sporadic optic pathway gliomas, neurofibromatosis 1-associated optic pathway gliomas tend to have a more indolent natural history (105) and there is general agreement that asymptomatic lesions do not require treatment. About 60% of patients with neurofibromatosis 1 with optic pathway glioma discovered on MRI will not develop vision loss, and imaging progression does not always correlate with vision loss. As such, a complete neuro-ophthalmological examination is the gold standard for diagnosis and follow-up of optic pathway glioma, with visual acuity being the most reliable measure of glioma stability or progression (105).

Chemotherapy. Chemotherapy is the predominant treatment modality for optic pathway gliomas. The current standard is carboplatin and vincristine, which have shown a progression-free survival of 68% at 3 years in children with nonresectable low-grade gliomas. Alternative regimens with similar efficacy include weekly vinblastine, adding temozolomide to carboplatin and vincristine, TPCV (thioguanine, procarbazine, CCNU [lomustine], and vincristine), as well as cisplatin and etoposide. A multicenter retrospective analysis of 115 patients with neurofibromatosis 1 with optic pathway glioma treated with chemotherapy found that visual acuity improved, remained stable, and declined in about 30% each, and that earlier treatment may be beneficial (39). In patients with neurofibromatosis 1 with progressive optic pathway glioma, bevacizumab and vinblastine have been reported to induce tumor regression or improve vision (30; 105). Ongoing chemotherapy trials include the use of lenalidomide (NCT01553149) and vinblastine ± bevacizumab (NCT02840409).

Radiation. Although radiotherapy with typical doses between 45 and 60 Gy in 1.6 to 2.0 Gy fractions has shown a 90% progression-free survival at 10 years, it is not recommended in patients with neurofibromatosis 1 due to significant associated risks, especially in young children. Long-term risks include neuroendocrine dysfunction, neurodevelopmental delay, cognitive effects, radiation-induced optic neuropathy causing further visual loss, Moyamoya syndrome, and secondary malignancy (18; 37; 105). The last two are of particular concern among patients with neurofibromatosis 1, who have over 3-fold increased risk of second nervous system tumors compared to non-neurofibromatosis 1 patients (101).

Surgery. Surgery should only be used in specific circumstances, including severe visual loss associated with painful proptosis, corneal exposure, or disfigurement, or with obstructive hydrocephalus necessitating debulking of the lesion.

Targeted therapy. Because genetic aberrations affecting the RAS-mitogen-activated protein kinase (MAPK) signaling pathway are hallmark features of both neurofibromatosis 1 and low-grade gliomas (including optic pathway glioma), therapies targeting activation of RAS and MAPK are of great interest. Dramatic responses have been reported in selected cases of neurofibromatosis 1-associated optic pathway glioma. A phase II study revealed that pediatric patients (3 to 21 years of age) with recurrent or progressive neurofibromatosis 1–associated low-grade gliomas had significant disease stability and shrinkage during treatment with oral everolimus, with a well-tolerated toxicity profile (112).

Ongoing phase II trials are investigating the role of the MEK1/2 inhibitor selumetinib in progressive/refractory low-grade gliomas in patients with neurofibromatosis 1 (NCT01089101; NCT03326388); the role of the MEK inhibitor trametinib alone (NCT03363217) or in association with hydroxychloroquine (NCT04201457); and binimetinib (NCT02285439). Preliminary results of the NCT01089101 trial have shown that 10 of the 25 (40%) patients with neurofibromatosis 1 with optic pathway gliomas achieved a partial response with selumetinib. Ongoing phase III trials are comparing outcomes between selumetinib and carboplatin/vincristine in patients with neurofibromatosis 1-associated low-grade gliomas (NCT03871257) (105).

Novel therapy. Ongoing phase II trial for progressive neurofibromatosis 1 low-grade gliomas include polyinosinic-polycytidylic acid stabilized with poly-L-lysine and carboxymethylcellulose (poly-ICLC; NCT04544007), a synthetic double-stranded RNA molecule with direct antineoplastic and immune-enhancing effect (62).

Future therapy/treatment advances/therapeutic development. Although the clinical outcome of malignant peripheral nerve sheath tumor has not changed substantially in the past 15 years, there has been progress in our understanding of the natural history, biology, and pathogenesis of these tumors. In 2016, an international meeting titled “MPNST State of the Science: Outlining a Research Agenda for the Future” was convened to develop research priorities for the next 10 years.

Over the last decade, there has been an explosion of clinical trials for neurofibromatosis-related tumors and conditions. The Neurofibromatosis Therapeutic Acceleration Program (NTAP) sponsors the Neurofibromatosis Preclinical Consortium, which has conducted 115 preclinical trials to date, and delivered 16 drugs to clinical pipeline, including the highly successful MEK inhibitors (92). Therapeutic development in neurofibromatosis 1 to date has been tumor specific and has focused on optic pathway glioma, plexiform neurofibroma, and malignant peripheral nerve sheath tumor, with a particular focus on targeted therapies and tumor microenvironment modulators.

MEK inhibitors have shown activity in plexiform neurofibroma, low-grade glioma, and bone pathology preclinically. The MEK inhibitor selumetinib has now entered phase 2 clinical trials for plexiform neurofibromas and optic pathway gliomas (NCT02407405 and NCT01089101, respectively). Hence, there are new data to support the rationale that targeting of a key pathway affected by loss of neurofibromin will result in clinical benefit across a range of neurofibromatosis 1 manifestations (18). The farnesyl transferase inhibitor tipifarnib, which targets the first critical step (farnesylation) in the posttranslational modification of RAS, has been tested in a phase 2 trial demonstrating tolerability but no significant prolongation of time to progression in progressive plexiform neurofibroma (116). The importance of the microenvironment has been highlighted in tumor formation, notably microglial cells in optic pathway glioma and mast cells in plexiform neurofibromas. Furthermore, imatinib (a c-kit inhibitor, involved in mast cell development) was assessed in a clinical trial of symptomatic plexiform neurofibromas, resulting in at least a 20% decrease in tumor volume in 6 of 36 patients (60).

One limitation to progress in the field of neurofibromatosis developmental therapeutics is that some neurofibromatosis 1-associated brain tumors (eg, optic pathway gliomas and brainstem gliomas) are rarely biopsied or surgically removed. To circumvent this particular issue, a multiinstitutional international study sequenced low-grade gliomas from children with neurofibromatosis 1 and demonstrated that most of these tumors harbored biallelic NF1 inactivation and were pilocytic astrocytomas, unlikely to harbor additional mutations. In contrast, tumors defined as nonpilocytic astrocytomas (approximately 10%) were more likely to harbor additional mutations such as FGFR1 and PIK3CA mutations. These findings support the current practice that biopsy is not indicated in the management of typically appearing neurofibromatosis 1 low grade gliomas in children as the likelihood of identifying an actionable mutation is low. Biopsy may be considered for tumors unresponsive to chemotherapy, with atypical radiological features, or located outside the optic pathway or hypothalamus. When done, testing for ATRX and CDKN2A alterations on biopsy is important as their presence defined the newly recognized high-grade astrocytoma with piloid features, and predicts poorer clinical outcomes (62).

Special considerations

Pregnancy

Fertility does not appear to be impaired in patients with neurofibromatosis 1 (106), but women with neurofibromatosis 1 need to be aware of the 50% risk of transmitting neurofibromatosis 1 for each pregnancy, as well as the increased risk of pregnancy complications, and of neurofibroma growth. Genetic counseling is recommended for every patient with neurofibromatosis 1 of childbearing age (37). Options that should be discussed include preimplantation genetic diagnosis to identify those embryos that do not carry a known familial NF1 mutation, and amniocentesis or chorionic villus sampling to obtain a sample for genotyping the fetus, if the precise mutation of an affected family member with neurofibromatosis 1 is known.

The current obstetrical literature indicates that women with neurofibromatosis 1 are at increased risk of pregnancy complications. Two large, retrospective, register-based population studies conducted in Finland and in the United States examined thousands of pregnancies and deliveries associated with neurofibromatosis 1 (106; 66). They reported increased maternal morbidity from gestational hypertension, preeclampsia, intrauterine growth restriction, cerebrovascular disease, preterm labor, and cesarean delivery, despite adjusting for multiple confounding factors such as preexisting chronic hypertension (4.7% vs. 1.8%) and renal disease (0.8% vs. 0.3%). No increased in maternal mortality was seen (14). Such data indicate that both providers and pregnant women with neurofibromatosis 1 should be aware of the potential for enhanced obstetrical risk and consider more frequent blood pressure monitoring and screening of other problems during pregnancy (14).

Multiple studies have shown an overall increase in number and size of neurofibromas in patients with neurofibromatosis 1 during pregnancy with, in some cases, postpartum regression. In a report of 247 pregnancies in 105 women, growth of new lesions and enlargement of existing lesions were reported in 60% and 55% of cases, respectively (35). One study more specifically demonstrated that during pregnancy there is an increase in cutaneous and plexiform neurofibromas as well as an increase in malignant transformation (90). In a review, these changes were thought to be secondary to two different factors: angiogenesis and hormonal effect. Increased hormonal stimulation during pregnancy may lead to worsening or progression of a patient's neurofibromatosis (96). An in vitro study highlighted the significance of sex hormones in the regulation of neurofibroma growth (86). It showed that the somatic second hit in the NF1 gene sensitizes Schwann cells to sex hormones (estradiol, testosterone, and human chorionic gonadotropin) resulting in a highly increased proliferation.

Anesthesia

Complications of neurofibromatosis 1 that could influence anesthesia include upper airway neurofibroma, severe kyphoscoliosis, hypertension, vasculopathy, mediastinal neurofibromas causing superior vena cava compression, and acute changes in blood pressure from pheochromocytoma and carcinoid tumors.

The preoperative evaluation should include a thorough review of systems, as well as blood pressure measurements, pulmonary function testing, prior echocardiography reports review, direct laryngoscopy examination, neck/chest CT or MRI to investigate for any respiratory complications, and spinal MRI to rule out spinal neurofibroma prior to epidural or spinal procedures.

During surgery, anesthesiologists must pay close attention to the heart rhythm and blood pressure and maintain a high index of suspicion for the possibility of pheochromocytoma and carcinoid tumors. Beta-blockers should also be used with caution in these patients because of the possibility of an undiagnosed pheochromocytoma.

Surgical removal of pheochromocytomas can result in hypertensive crisis, cardiac arrhythmias, and multiorgan dysfunction. The management of these patients is via administration of an alpha-antagonist days before surgery with the addition of a beta-blocker after the initiation of the alpha-antagonist. Intraoperative complications of carcinoid tumor removal include potentially fatal hypotension, cardiac arrhythmias, and bronchoconstriction. Successful anesthetic management involves the use of preoperative and intraoperative octreotide.