Version May 2024
INTRODUCTION — There are several clinically and genetically distinct forms of neurofibromatosis. Neurofibromatosis type 1 (NF1), previously known as von Recklinghausen disease, is the most common type. The hallmarks of NF1 are the multiple café-au-lait macules and associated cutaneous neurofibromas. The condition is called segmental NF1 when clinical features are limited to one area of the body due to somatic mosaicism of a pathogenic NF1 gene variant.
The management and prognosis of NF1 are reviewed here. The pathogenesis, clinical features, and diagnosis are discussed separately (see "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis"). The schwannoma predisposition syndromes, including NF2-related schwannomatosis (NF2, formerly neurofibromatosis type 2), are also discussed in detail separately. (See "NF2-related schwannomatosis (formerly neurofibromatosis type 2)" and "Schwannomatoses related to genetic variants other than NF2".)
SURVEILLANCE FOR COMPLICATIONS — Persons with NF1 should be cared for by a multidisciplinary team of dedicated specialists throughout their lifetime [1]. Longitudinal care for persons with NF1 aims at the early detection and symptomatic treatment of complications as they occur. The decision to obtain testing such as imaging studies depends upon the history and physical findings. Clinical evaluation appears to be more useful to detect complications than are surveillance investigations in asymptomatic patients [2,3]. Thus, for example, pediatric care guidelines do not recommend neuroimaging as a surveillance modality for optic pathway gliomas (OPGs) [1], although not all clinicians agree. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Optic pathway gliomas' and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Bone abnormalities'.)
Annual surveillance for all children with NF1 — Consensus clinical guidelines from the American Academy of Pediatrics and the American College of Medical Genetics and Genomics are available [1]. Regular visits at yearly intervals should include:
●Physical examination:
•Examine skin for new neurofibromas, signs of plexiform neurofibromas (PNs), or progression of existing lesions. (See 'Malignant peripheral nerve sheath tumors' below.)
•Check blood pressure for signs of hypertension [4]. (See 'Severe hypertension' below.)
•Evaluate growth measurements including height, weight, and head circumference. (See 'Optic pathway gliomas' below and 'Brain tumors and hydrocephalus in patients with seizures or progressive macrocephaly' below.)
•Evaluate for skeletal changes, including scoliosis, vertebral changes, and limb abnormalities, particularly tibial dysplasia in young patients.
●A formal ophthalmologic examination, including visual screening. (See 'Optic pathway gliomas' below.)
●Assessment for precocious puberty. Evaluate older children for early development of secondary sexual characteristics or abnormal growth acceleration that may be associated with lesions of the pituitary from optic glioma involving the chiasm. (See 'Optic pathway gliomas' below.)
●Developmental assessment. Evaluate neurodevelopmental progress and evidence for attention-deficit disorder. (See 'Cognitive and learning deficits' below.)
●Review of school progress. (See 'Cognitive and learning deficits' below.)
●Monitoring of PNs. Affected persons and, for pediatric patients, their parents/caregivers should be questioned, particularly in adolescence, about any change in pain or growth pattern associated with a preexisting PN and, if found, should be evaluated for possible malignant transformation of the neurofibroma. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Plexiform neurofibromas' and 'Malignant peripheral nerve sheath tumors' below.)
Surveillance for adults with NF1 — An expert panel of the American College of Medical Genetics and Genomics has formulated guidelines for the care of adults with NF1 [5]. Surveillance measures for the following complications were highlighted:
●Malignant peripheral nerve sheath tumor (MPNST):
•MPNST often arise from PNs. Thus, imaging is indicated for symptomatic PN (eg, progressive severe pain, rapid tumor growth, nodularity, new neurologic symptoms). Imaging of an asymptomatic PN is also reasonable if a deeper component is suspected. (See 'Malignant peripheral nerve sheath tumors' below.)
•The term "atypical neurofibromatous neoplasms of uncertain biologic potential" (ANNUBP) was proposed in 2016 after a consensus meeting to describe lesions that pose diagnostic challenges [6]. This diagnosis should prompt additional sampling, clinical correlation, and possibly expert pathology consultation.
•Magnetic resonance imaging (MRI) is the preferred method of imaging if MPNST is suspected. 18-F fluorodeoxyglucose positron emission tomographic (FDG-PET) scanning is helpful in distinguishing MPNST from a benign PN [7-10].
●Breast cancer:
•Women with NF1 are at increased risk of breast cancer and may present at an earlier age than the general population, at approximately 40 years of age, with the earliest cases reported at approximately 30 years of age. Women with NF1-related breast cancer have a significantly poorer five-year survival and excess mortality [11].
•The National Comprehensive Cancer Network guidelines recommend an annual mammogram starting at age 30 years and suggest contrast-enhanced breast MRI between ages 30 and 50 years for women with a clinical diagnosis of NF1 [11].
●Pheochromocytoma:
•Adults with NF1 over 30 years of age or who are pregnant and who have hypertension or associated symptoms of palpitations, headache, or diaphoresis should have measurement of plasma-free fractionated metanephrines to assess for pheochromocytoma; this test is considered the most sensitive screening test. Persons with an equivocal screening test (less than fourfold elevation) should have a 24-hour urine collection for catecholamines and metanephrines and/or imaging screening [12,13].
•Biochemical or imaging screening for pheochromocytoma is not recommended for asymptomatic patients, although emerging literature supports screening for pheochromocytoma in persons with NF1 prior to surgical procedures, pregnancy, labor, and delivery since these procedures can trigger cardiovascular crisis [12,13].
●Hypertension:
•Persons with NF1 have higher risk for vasculopathy, which may manifest as renal artery stenosis with consequent hypertension, vascular occlusion, aneurysms, or arteriovenous fistulae.
•Overall estimated incidence of vasculopathy in NF1 is 0.4 to 6.4 percent; the estimated incidence of cerebrovascular vasculopathy is 2 to 5 percent, with hemorrhagic strokes more predominant in both children and adults [14].
•Blood pressure should be measured at least annually in persons with NF1 since there is an increased risk of renovascular hypertension, particularly due to renal artery stenosis, in younger adults. Hypertension in adults with NF1 is usually primary (essential), but these persons should still be screened for renovascular disease, particularly if they are <30 years of age, pregnant, or have abdominal bruits.
•Either spiral computed tomography (CT) with contrast (CT angiography) or contrast-enhanced magnetic resonance angiography (MRA) can be used to evaluate for renal artery stenosis in patients with normal renal function. We use time-of-flight MRA (which is a noncontrast study) in those with abnormal renal function. Renal angiography is an option in persons with negative imaging but in whom renal artery stenosis is still suspected. Early detection of vasculopathies and medical and/or surgical interventions may prevent hypertension-related complications; hence, selective vascular imaging should be performed in persons with physical findings suggestive of vascular lesions.
●Osteoporosis and scoliosis:
•Adults should be monitored for osteoporosis.
•All persons with NF1 should be screened annually for scoliosis. Adults with scoliosis should be monitored for curve progression.
●Neurocognitive and psychiatric problems:
•Screening for depression is suggested for adults with NF1.
•Clinicians should be alert to the possibility of attention-deficit disorder.
•Cognitive impairment is common in persons with NF1, and intelligence quotient (IQ) may be reduced; however, more severe cognitive impairment should prompt the evaluation for other etiologies.
●Chronic pain:
•Chronic pain is common in adults with NF, but new-onset pain of increasing severity may indicate an MPNST and warrants evaluation.
•Fingertip or toe pain may indicate the presence of glomus tumors.
●Reproductive issues:
•Preanesthesia neuraxial imaging is usually not necessary if spinal anesthesia is planned for labor and delivery.
•Adults with NF1 should be counseled about risks of genetic transmission and options for prenatal or preimplantation diagnosis.
Surveillance for specific complications or presentations
Optic pathway gliomas — Because of the variable natural history of OPGs, all children with NF1 should undergo thorough ophthalmologic evaluation and regular assessments of height and pubertal development [15-19]. Ideally, ophthalmologic screening should include visual acuity testing, confrontation visual field testing, color vision testing, and assessment of pupils, eyelids, irises, fundi, and extraocular motility, although the full range of assessment may not be feasible in the infant or young child. The evaluation should begin when NF1 first is suspected and be repeated at annual intervals or when symptoms develop. In addition, patients with OPG may show evidence of central precocious puberty, diencephalic syndrome, growth hormone deficiency, or excess growth hormone [19,20].
Any child with visual symptoms or physical signs (eg, proptosis, decreased visual acuity, precocious puberty, or abnormal growth patterns) should have an MRI of the brain and orbits to investigate for an OPG. OPGs appear as an enlargement of the optic nerve or chiasm on MRI. A consensus panel convened by the Children's Tumor Foundation did not recommend neuroimaging for surveillance in asymptomatic children with NF1 [17], and many neurofibromatosis clinics follow young children with NF1 according to these guidelines [21]. Others have employed protocols that include MRI of the brain and orbits in addition to ophthalmologic examination [22].
Clinical observations suggest that systematic surveillance for OPG, particularly in the first 18 months of life, permits early intervention and may reduce complications. The outcome of systematic surveillance for OPG with MRI and ophthalmic examinations in young children with NF1 was evaluated in a clinical study of children less than six years of age [23]. OPG were detected in 9 of 69 children who were asymptomatic and had normal ophthalmic examinations (13 percent). Three of these children were treated with chemotherapy (due to progression of the lesion on subsequent MRI and/or ophthalmic examination) and retained normal visual function. A subsequent review of 826 children with NF1 who had routine MRI surveillance at one center revealed optic pathway tumors in 18 percent, with a median age of diagnosis of three years [22]. Children with no evidence of an optic pathway tumor by 18 months of age did not subsequently develop one. If this finding is confirmed, it might justify MRI screening to obviate the need for ophthalmologic follow-up in the 80 percent or more who will not have tumors. In any case, there is a consensus that it is important to make the clinical diagnosis of NF1 in very young children so that ophthalmic evaluations are initiated.
There is little consensus regarding the frequency of visual examinations and neuroimaging for children with NF1 in whom OPGs have been identified [17]. Suggested intervals have varied [24-27]. Measurement of retinal nerve fiber thickness may be helpful in sensitive detection of loss of visual acuity in children with optic gliomas [28]. The treatment of OPGs is discussed separately. (See "Optic pathway glioma", section on 'Treatment'.)
Brain tumors and hydrocephalus in patients with seizures or progressive macrocephaly — An MRI of the brain should be performed when seizures are first diagnosed given the increased risk for central nervous system (CNS) tumors in NF1 [29]. A child with acute acceleration in head growth should be evaluated for hydrocephalus due to aqueductal stenosis and CNS neoplasms [30]. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Other central nervous system neoplasms' and "Hydrocephalus in children: Clinical features and diagnosis".)
Malignant peripheral nerve sheath tumors — Some experts suggest MRI screening for MPNSTs [31]. Such screening is not incorporated into NF1 guidelines, given the long period of risk (adolescence through mid-adulthood) and the variable location of tumor development. Primary care clinicians, parents/caregivers, and children entering adolescence should be educated about the risk of MPNST and strongly encouraged to report the development of any signs or symptoms suggestive of an MPNST (eg, pain, unexpected growth of a tumor, or change in texture from soft to firm) to a clinician familiar with NF1. Prompt investigation, including MRI [32] and, if concerning features are noted on imaging, FDG-PET, should be initiated in symptomatic patients. Although MRI cannot reliably distinguish benign neurofibromas from MPNSTs, use of diffusion-weighted MRI may be useful in detection of MPNST [33].
Studies have explored modalities to identify precursor lesions to MPNSTs in persons at high risk for these tumors because of NF1 microdeletions, ANNUBP, prior radiation therapy, and/or higher internal tumor burden of neurofibromas [34]. Those persons should undergo regular screening using MRI and/or 18F-FDG-PET SUVmax. Moreover, some experts recommend whole-body MRI at the age of 16 to 20 years to plan surveillance in adulthood and help identify high-risk groups [35]. Emerging technical advances, such as whole-body MRI combined with diffusion-weighted imaging/apparent diffusion coefficient (DWI/ADC) mapping, PET/MRI, as well as clinical and genetic data, can provide more insight into tumor characteristics [6,36-38].
Biopsy of several sites within a preexisting PN may be indicated to determine if malignant transformation has occurred.
Pheochromocytoma in patients with GIST — Although pheochromocytomas are a rare finding in patients with NF1, there was a frequent co-occurrence of gastrointestinal stromal tumors (GISTs) and pheochromocytoma in one series, suggesting that any patient undergoing surgical procedures for a GIST should be first screened for the presence of a pheochromocytoma [39].
Gastrointestinal symptoms — Both children and adults may complain of symptoms of gastrointestinal discomfort, including constipation, irritable bowel syndrome, and functional dyspepsia [40,41]. There are no formal recommendations for surveillance or testing, but clinicians should be aware that children with NF1 are at increased risk for these disorders so that they can be diagnosed and treated appropriately.
Muscle weakness — Children with NF1 often display generalized muscle weakness and consequent motor developmental delay [42,43]. Muscle biopsy studies have revealed signs of lipid storage myopathy in some affected individuals [44]. A small clinical trial has shown evidence for potential benefit of L-carnitine supplementation in improving muscle strength [45], though confirmation in a larger group of children is required.
Severe hypertension — The most common causes of hypertension in NF1 are essential hypertension, pheochromocytoma, and, in adults <30 years of age, renal artery stenosis. Persons with severe hypertension, particularly adults <30 years of age, should be evaluated for renal artery stenosis. If that screening is negative, then patients should be evaluated for pheochromocytoma. Correction of the underlying lesion typically lowers the blood pressure in patients with renal artery stenosis or pheochromocytoma [46]. (See "Ambulatory blood pressure monitoring in children" and "Nonemergent treatment of hypertension in children and adolescents" and "Evaluation of hypertension in children and adolescents" and "Pheochromocytoma and paraganglioma in children" and 'Surveillance for adults with NF1' above.)
Cognitive and learning deficits — Children with NF1 should be monitored for developmental progress. One analysis of 66 children with NF1 found that autism spectrum disorder (ASD) related symptoms were common, with one-third of the patients at risk for clinically significant ASD symptoms [47]. A careful neurologic examination should be part of the evaluation performed at yearly intervals. A developmental history should be obtained, and school progress reviewed. If areas of concern are identified, a formal educational assessment should be performed [48]. IQ testing and neuropsychologic evaluation may identify cognitive deficits early and facilitate the use of academic support in school [2]. Neuroimaging should not be part of a routine diagnostic evaluation, because of the uncertain relationship between MRI findings and learning disabilities. MRI should be performed to evaluate specific neurologic deficits, such as loss of coordination.
Pregnant women with NF1 — Women with NF1 are at increased risk for morbidity, particularly hypertensive and vascular complications, but not mortality during pregnancy [49,50]. Pregnant women with NF1 may benefit from management by a high-risk obstetrical service. Pregnant women with NF1 should be aware of the autosomal-dominant inheritance of the condition and the 50 percent chance that their baby will inherit the condition. Steps should be taken to ensure appropriate surveillance for the newborn infant. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Epidemiology' and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Pathogenesis' and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Clinical manifestations' and 'Surveillance for adults with NF1' above.)
TREATMENT — There is no one overall treatment for NF1, although the use of mitogen-activated protein kinase kinase (MAPKK or MEK) inhibitors is changing the approach to management of plexiform neurofibromas (PNs) (see 'Plexiform neurofibromas' below). Clinical trials are ongoing for some clinical problems associated with the disorder [51].
Tumors — The approach to treatment of the various tumors associated with NF1 depends upon the type of tumor, its effect on adjacent tissues, and related complications. Minimization of radiation treatment is a goal when planning treatment of patients with NF1 and central nervous system (CNS) tumors because of concerns about secondary CNS malignancies and vascular complications [52-54]. There is no evidence that specific NF1 mutations are associated with differential sensitivity to radiation or chemotherapy or predict response to treatment.
Cutaneous and subcutaneous neurofibromas — Cutaneous and subcutaneous neurofibromas are not removed unless there is a specific need for removal (eg, pain, bleeding, interference with function, disfigurement) [55]. Various options for removal, such as surgery, laser removal, or electrodessication, are available, although long-term outcomes are not documented [5]. Some patients experience pruritus that does not usually respond to antihistamine treatment but may improve with medications used to treat neuropathic pain, such as gabapentin. (See "Peripheral nerve tumors", section on 'Neurofibroma'.)
Plexiform neurofibromas — PNs usually involve multiple nerve fascicles, with serpiginous growth and significant vascularity. Multiple morbidities may occur, including pain, motor dysfunction, and visual loss [56], and worsening morbidity is associated with growth of the lesions [57]. PNs also can undergo malignant transformation to malignant peripheral nerve sheath tumors (MPNSTs) [58]. Surgical treatment and pain management of PNs can be a significant challenge, especially when there is progressive growth along the spinal column that results in compression of the spinal cord [59,60]. Selumetinib, an oral selective mitogen-activated protein kinase kinase (MEK) inhibitor that can induced tumor regression, was approved by the US Food and Drug Administration (FDA) in April 2020 for the treatment of pediatric patients age three years or older with symptomatic and/or progressive, inoperable NF1-related PNs [61]. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Soft tissue sarcomas'.)
Selumetinib is used in patients with symptomatic and inoperable tumors. In a phase II multicenter trial, 50 children aged 2 to 18 years with NF1 and inoperable PNs were treated with selumetinib at a dose of 25 mg/m2 by mouth twice daily [62]. A partial response, defined as a ≥20 percent decrease in tumor volume from baseline for at least four weeks, was observed in 70 percent of patients and was durable (lasting ≥1 year) in 80 percent. Mean tumor-related pain intensity scores decreased by two points after one year of treatment, and approximately 50 percent of patients experienced improvements in functional outcomes and quality of life. With longer-term follow-up in 74 children treated on phase I and II trials (median duration of treatment 57.5 monthly cycles), tumor responses were largely maintained, with 59 percent lasting 12 or more cycles [63]. Improvements in tumor pain were also sustained.
The most common clinical toxicities of MEK inhibitors are gastrointestinal, increased creatine phosphokinase (CPK), and dermatologic. Based on pooled data from over 125 treated patients, the most common adverse effects of selumetinib in patients with NF1 are diarrhea (64 percent), elevated CPK (63 percent, majority asymptomatic), acneiform rash (54 percent), mucositis (43 percent), and paronychia (41 percent) [64]. Less common but serious toxicities of selumetinib include reduced left ventricular ejection fraction and cardiomyopathy and ocular toxicity (eg, retinal detachment). No new safety signals have appeared with up to five years of treatment [63].
Clinical trials to treat PNs with other targeted therapies are ongoing. The MEK inhibitor mirdametinib was tested in a clinical trial for treatment of PN [65]. Eight of 19 participants experienced a 20 percent or greater decrease in tumor volume over the course of the study. Cabozantinib, a multiple tyrosine kinase inhibitor with targets that include cMET and vascular endothelial growth factor receptor 2 (VEGFR2), has also shown promising activity [66].
Treatment with imatinib or pegylated interferon has resulted in shrinkage of PNs in a limited number of patients with NF1 and PNs [67-69]. Clinical trials in patients with NF1 and PNs with the farnesyl transferase inhibitor tipifarnib [49,70], the mammalian (mechanistic) target of rapamycin (mTOR) inhibitor sirolimus, and the fibroblast inhibitor pirfenidone [71-73] have not demonstrated sufficient benefit to warrant clinical use.
Clinicians can use the ClinicalTrials.gov website to inquire about open clinical trials for patients with NF1.
Surgical resection often is limited to debulking of a specific area of a large lesion, for example, when a component is impinging on the spinal cord or airway or a large soft tissue component is removed to improve cosmesis. In several series, patients were more likely to benefit from surgery when the indications were airway compression or disfigurement [59,60]. The management of chronic pain is discussed in detail separately. (See "Pain in children: Approach to pain assessment and overview of management principles" and "Approach to the management of chronic non-cancer pain in adults".)
Optic pathway gliomas and other low-grade gliomas — NF1-associated low-grade gliomas (LGGs) in pediatric and adolescent patients usually behave in an indolent manner. Optimal management of LGGs is controversial. If possible, a period of observation with close monitoring of tumor size, visual function, and symptomatic progression should precede treatment initiation. When treatment is deemed necessary, first-line therapy traditionally consists of chemotherapy with carboplatin and vincristine [52,53,74]. Vinblastine monotherapy has also been shown to be effective [74].
Targeted agents are under investigation. The Pediatric Brain Tumor Consortium performed a phase II study assessing the activity of selumetinib in patients with recurrent, refractory, or progressive LGGs, including a stratum dedicated to patients with NF1-associated LGGs [75]. In this stratum, 10 of 25 patients achieved a sustained partial response. This has led to the ongoing Children's Oncology Group study (ACNS1831), which randomly assigns patients with previously untreated NF1-associated LGGs to standard-of-care carboplatin/vincristine therapy or selumetinib. The mTOR inhibitor, everolimus, has also shown efficacy. In a multicenter phase II trial in 23 patients with recurrent/progressive NF1-associated LGGs, 15 of 22 patients demonstrated a clinical response to oral everolimus (1 complete response, 2 partial responses, 12 with stable disease) [76].
For adults, there is no specific treatment for NF1-associated LGGs. They are generally treated according to the histologic pathology; patients with pilocytic astrocytomas are often managed with surveillance, while those with diffuse LGGs may be offered treatment with radiation [77].
Contrary to previous literature, approximately one-third of patients with progressive optic pathway glioma (OPG) treated with chemotherapy may regain some lost vision [78,79]. Radiation is avoided in pediatric patients with NF1 due to the increased risk of secondary malignancy and moyamoya [52,54,80]. Alkylating agents have typically been avoided as well due to concern for secondary malignancy; however, a retrospective analysis did not find a significantly increased risk of secondary neoplasm associated with the use of alkylating agents in patients with NF1 [54].
The surveillance for and monitoring of OPGs are discussed above, and treatment is discussed in greater detail separately. (See 'Optic pathway gliomas' above and "Optic pathway glioma", section on 'Treatment'.)
High-grade gliomas — When a high-grade glioma (HGG) is suspected, biopsy or surgical resection is recommended. There is tremendous variability in treatment practices for HGGs. Pediatric HGGs are treated similar to sporadic cases with maximum safe surgical resection and usually radiation therapy [81]. Adults with HGGs are usually offered conventional radiation, at times with concurrent temozolomide.
The observed age of occurrence of NF1-associated glioblastoma in adults, mean of 38.3 years, is much younger than the mean age for patients with sporadic glioblastoma. There is evidence that NF1-associated glioblastoma may comprise a unique subset of isocitrate dehydrogenase (IDH) wildtype tumors [82]. Treatment will likely continue to evolve given the advancing molecular understanding of NF1-related tumors and targeted therapies [77].
Malignant peripheral nerve sheath tumors — MPNSTs are staged and treated as malignant soft tissue sarcomas [83]. Treatment includes surgical resection and adjunctive radiation therapy. A study of the utility of preoperative imaging to detect atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP) using magnetic resonance imaging (MRI) and 18F-FDG-PET SUVmax demonstrated the feasibility of safe fascicle-sparing marginal resection with intraoperative nerve stimulation and microdissection of nerve fascicles [84]. This approach can theoretically prevent progression to MPNST. The use of chemotherapy for high-grade, unresectable MPNST is also under investigation. A preclinical study showed dramatic tumor shrinkage in a transgenic MPNST mouse model in response to combined HSP90 and mTOR inhibition [85]. Despite the promising preclinical rationale and tolerability, a phase I/II study of ganetespib, a novel injectable inhibitor of HSP90 and the mTOR inhibitor, sirolimus failed to show a response (NCT02008877) [86,87]. Another novel approach undergoing phase I study uses the oncolytic potential of the genetically engineered injectable measles virus Edmonston vaccine strain (MVEdm) that encodes thyroid sodium iodide symporter [88]. (See "Peripheral nerve tumors", section on 'Treatment of MPNSTs' and "Peripheral nerve tumors", section on 'Prognosis' and "Treatment of locally recurrent and unresectable, locally advanced soft tissue sarcoma of the extremities" and "Overview of the initial treatment of metastatic soft tissue sarcoma".)
Rhabdomyosarcoma — Treatment of rhabdomyosarcoma includes chemotherapy, surgery if feasible, and radiation therapy. These are discussed in greater detail separately. (See "Rhabdomyosarcoma in childhood, adolescence, and adulthood: Treatment".)
Gastrointestinal stromal tumors — Most gastrointestinal stromal tumors (GISTs) in patients with NF1 do not carry somatic mutations in the v-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homologue (KIT) or platelet-derived growth factor receptor alpha (PDGFRA) genes, unlike GISTs that arise outside of the setting of NF1 [89,90]. Consistent with this finding, these tumors in patients with NF1 are poorly responsive to the tyrosine kinase inhibitor imatinib [90,91]. (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors" and 'Pheochromocytoma in patients with GIST' above.)
Neurologic abnormalities — Neurologic disorders that may require specific management include cognitive deficits, learning disabilities, seizures, and peripheral neuropathy. Adults with NF1 are also at risk for headaches, including migraines, and sleep disorders, which are managed the same as in the general population.
Cognitive and learning deficits — Children with learning disabilities should receive academic support. Speech, occupational, and physical therapy should be provided for children with speech problems and motor impairment involving balance and gait. Some children have attention-deficit disorder, with or without hyperactivity, which may respond to stimulant medication [92,93]. (See "Attention deficit hyperactivity disorder in children and adolescents: Overview of treatment and prognosis" and "Attention deficit hyperactivity disorder in children and adolescents: Treatment with medications", section on 'Stimulants versus other medications' and "Attention deficit hyperactivity disorder in children and adolescents: Clinical features and diagnosis", section on 'Core symptoms' and "Attention deficit hyperactivity disorder in children and adolescents: Clinical features and diagnosis", section on 'Clinical features'.)
Statin drugs were hypothesized to be a potential treatment for cognitive and learning deficits in NF1 based on preclinical mouse model data [94], but two randomized trials in children with NF1 failed to confirm a benefit [95-97].
Seizures — The management of seizures in patients with NF1 is similar to that of seizures due to other causes and is discussed in detail separately. (See "Seizures and epilepsy in children: Initial treatment and monitoring" and "Overview of the management of epilepsy in adults".)
Peripheral neuropathy — Management of peripheral neuropathies involves treatment of the underlying disease process, if possible (eg, nerve compression due to a tumor), and alleviation of symptoms. A generalized polyneuropathy may occur in some adults in the absence of a compressive lesion [98-100]. (See "Overview of polyneuropathy" and "Pain in children: Approach to pain assessment and overview of management principles" and "Approach to the management of chronic non-cancer pain in adults", section on 'General approach'.)
Bone abnormalities — Orthopedic intervention may be needed for tibial or other long-bone dysplasia and scoliosis. Other bone abnormalities, such as osteoporosis, may not respond as well to typical therapies, although further studies are needed. Vitamin D supplementation is advised for all persons with NF1 and vitamin D deficiency or insufficiency. Treatment of osteoporosis with calcium and vitamin D alone did not appear to increase bone density in a small trial [101]. Studies are needed to determine whether early intervention with bisphosphonates is indicated. (See "Vitamin D insufficiency and deficiency in children and adolescents" and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)
Pseudoarthrosis — Mobility may be improved by amputation of the lower leg and replacement with a prosthesis in some patients with tibial pseudoarthrosis [102]. A number of other surgical and pharmacologic approaches to managing tibial pseudoarthrosis are under investigation [103]. If possible, these patients should be evaluated by an orthopedics team that has experience with NF1, given the complexity of these lesions.
Short stature — Growth hormone therapy for short stature may be used to bring growth hormone to physiologic levels. Although concern has been raised that growth hormone could lead to tumor growth, there are no studies demonstrating that this has occurred. (See "Growth hormone treatment for idiopathic short stature".)
Scoliosis — Screening for spine deformity by physical examination should begin at diagnosis and be repeated yearly. To limit radiation exposure in the pediatric population, consensus-based guidelines recommend diagnostic spine imaging only if clinical suspicion arises from patient history or physical examination [104]. Orthopedic intervention, such as bracing or surgery, may be needed for scoliosis [105,106]. Spinal tumor burden must be assessed preoperatively in any patient with NF1 undergoing surgery for scoliosis. Magnetically controlled growing rods (MCGR) impede visualization of spinal tumors by MRI, especially intraspinal tumors, and MCGRs are not recommended when spinal tumor burden is high [104]. (See "Adolescent idiopathic scoliosis: Management and prognosis", section on 'Treatment modalities'.)
The requirement for surgical management of dystrophic scoliosis may further complicate the clinical picture of chronic pain management for persons with NF1 [107]. (See "Pain in children: Approach to pain assessment and overview of management principles" and "Approach to the management of chronic non-cancer pain in adults".)
Psychosocial issues — Specific counseling may be warranted for patients, particularly adolescents, with NF1 who face issues with self-esteem and the psychosocial impact of this condition [108,109].
Hypertension — The general management of primary hypertension and hypertension associated with renovascular disease or pheochromocytoma is discussed in detail separately. (See "Nonemergent treatment of hypertension in children and adolescents" and "Choice of drug therapy in primary (essential) hypertension" and "Treatment of unilateral atherosclerotic renal artery stenosis" and "Treatment of bilateral atherosclerotic renal artery stenosis or stenosis to a solitary functioning kidney" and "Treatment of pheochromocytoma in adults" and "Initial management of hypertensive emergencies and urgencies in children", section on 'Hypertensive emergency'.)
Pulmonary complications — Pulmonary complications include neurofibromas, cysts, emphysematous changes, and fibrosis [110-112]. Although these are rare, they can cause significant morbidity and even mortality. Treatment for these complications is the same as for pathologically similar pulmonary problems in the general population.
GENETIC COUNSELING — NF1 has an autosomal-dominant inheritance pattern. Counseling should be provided for patients and families. It should include information on the inheritance of the disorder (including potential recurrence risk in other offspring), prognosis, and psychosocial adjustment. The progressive nature of the disease and the variability in clinical presentation should be addressed. (See "Genetic testing".)
Reproductive decisions by couples are facilitated by appropriate genetic counseling about the availability of prenatal or preimplantation testing (see "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Prenatal testing' and "Genetic counseling: Family history interpretation and risk assessment"). Prospective parents should be aware that NF1 exhibits wide clinical variability within families and that establishing the diagnosis prenatally cannot predict the severity or outcome. The couple should also be informed that their risk of having an affected child can be substantially lowered by use of other reproductive technologies, including sperm or oocyte donation, depending upon which parent is affected. (See "In vitro fertilization: Overview of clinical issues and questions", section on 'When are donor oocytes used?' and "Donor insemination".)
The risk of having this disorder in each offspring of an affected parent is 50 percent. If a couple has one child with NF1 and neither parent meets the clinical criteria for NF1 (see "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Diagnostic criteria'), the risk of the parents having another child with NF1 is less than 1 percent. When this occurs, it is most often caused by germline mosaicism such that a proportion of the gonadal tissue contains the mutation [113,114]. The rate of germline mosaicism in NF1 is much lower than in NF2, osteogenesis imperfecta, and some other dominant disorders [115].
The risk of having a child with generalized NF1 is substantially reduced for patients with segmental disease (0 to 50 percent) compared with generalized disease (50 percent), but it is not possible to quantify a precise risk. Animal studies suggest that the risk is proportional to the percentage of body area involved [116]. If a person with segmental NF1 has an affected offspring, that child will carry the mutation in all cells of the body and will have generalized NF1, not segmental disease.
The Children's Tumor Foundation provides information about the disorder and general support. Referral of the family to a local chapter often is helpful.
PROGNOSIS — Survival data in persons with NF1 are limited, although several studies have highlighted the decreased life expectancy in persons with NF1, particularly women, compared with the general population [117-119].
In one report using data from United States death certificates from 1983 through 1997, the age at death was reduced for NF1 patients compared with that of the general population (median 59 versus 74 years, respectively) [117]. NF1 patients were more likely to have a malignant neoplasm listed on their death certificates, especially if death occurred before they reached 30 years of age. Similarly, in large cohort studies, the disease-specific survival of patients with NF1 who develop cancer is lower than that of comparable patients with sporadic cancers [119,120].
Prognosis of CNS tumors — The natural history of central nervous system (CNS) tumors in persons with NF1 is not well documented.
In a retrospective French study, treatment was undertaken in the minority of patients with both optic pathway glioma (OPG) and extraoptic pathway tumors [121]. Despite this, the 5- and 10-year survival rates were 90 and 82 percent when all patients were considered. Factors associated with significantly shorter survival were extraoptic location and tumor diagnosis in adulthood. Growth hormone deficiency (46 percent) and ischemic stroke (32 percent) were frequent complications of radiotherapy in patients with OPG.
Patients with NF1 and CNS tumors are at increased risk for early mortality, second CNS malignancies, and vascular complications [52,122]. In one report of 154 NF1 patients with OPG, 11 percent had a second CNS tumor [123]. The risk of non-CNS tumors was not increased by the presence of an optic pathway tumor.
OPGs appear to have a more benign course in patients with NF1 than in those without NF1, but there may be a degree of ascertainment bias since patients with NF1 are screened for OPGs, whereas sporadic cases are only identified when they are symptomatic or a brain scan is undertaken for other reasons. (See "Optic pathway glioma".)
The behavior and prognosis of extraoptic gliomas in adults with NF1 are variable [121]. NF1-associated low-grade gliomas (LGGs) in adults may behave more aggressively than their histology may predict [124]. Conversely, there is some evidence indicating that adults with NF1 and high-grade gliomas (HGGs) may have better outcomes than HGGs in the general population [125]. Studies evaluating alternative lengthening of telomeres (ALT) and loss of ATRX, an X-linked helicase, indicate that these alterations are predictive of aggressive behavior in NF1-associated gliomas. Specifically, ALT is present in 60 percent of histologically defined HGGs, but only 19 percent of histologically defined LGGs. ALT was independently associated with worse survival accounting for grade and age [77,126].
Prognosis of MPNST — Malignant peripheral nerve sheath tumor (MPNST) is an aggressive and potentially fatal malignancy. Outcomes are generally poor for patients that are not able to have complete resection. Historically, survival rates in patients with NF1 were lower than in patients with sporadic MPNST [31,127]. This difference has all but disappeared, with significantly improved survival rates seen in patients with NF1 since the early 2000s [83,128,129]. Three-year disease-specific survival was 64 percent in one series, and five-year overall survival was approximately 40 to 55 percent in two other series. (See "Peripheral nerve tumors", section on 'Prognosis'.)
Prognosis of rhabdomyosarcoma — Treatment outcomes for rhabdomyosarcoma in patients with NF1 appear similar to those in the general population with rhabdomyosarcoma [127]. (See "Rhabdomyosarcoma in childhood, adolescence, and adulthood: Treatment".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neurofibromatosis type 1".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Neurofibromatosis type 1 (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Longitudinal care – Longitudinal care for persons with neurofibromatosis type 1 (NF1) aims at the early detection and symptomatic treatment of complications as they occur. In providing medical supervision to children with NF1, the frequency of follow-up visits should increase to address disease complications as they arise. (See 'Annual surveillance for all children with NF1' above and 'Surveillance for adults with NF1' above.)
The decision to obtain diagnostic studies depends upon the history and physical findings. Clinical evaluation appears to be more useful to detect complications than are screening investigations in asymptomatic patients. (See 'Surveillance for specific complications or presentations' above.)
●Treatment of complications
•Tumors – The approach to treatment of the various tumors associated with NF1 depends upon the type of tumor, its effect on adjacent tissues, and related complications. Surgical treatment and pain management of plexiform neurofibromas (PNs) can be challenging. Surgical resection often is limited to debulking of a specific area of a large lesion. Progressive or symptomatic plexiform neurofibromas may be treated with mitogen-activated protein kinase kinase (MEK) inhibitors. (See 'Tumors' above.)
•Neurologic disorders – Neurologic disorders that may require specific management include cognitive deficits, learning disabilities, seizures, and peripheral neuropathy. (See 'Neurologic abnormalities' above.)
•Bone abnormalities – Orthopedic intervention may be needed for long bone dysplasia and scoliosis. Other bone abnormalities, such as osteoporosis, may not respond as well to typical therapies. (See 'Bone abnormalities' above.)
●Counseling – Counseling should be provided for affected persons and families. It should include information on the inheritance of the disorder, prognosis, and psychosocial adjustment. The progressive nature of the disease and its clinical manifestations and complications should be addressed. (See 'Psychosocial issues' above and 'Genetic counseling' above.)
●Prognosis – Information about the effect of NF1 on mortality is limited, although life expectancy appears to be shortened. Malignant neoplasms, particularly malignant peripheral nerve sheath tumors (MPNST), are the primary cause of decreased survival. (See 'Prognosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Sharon E Plon, MD, PhD, who contributed to an earlier version of this topic review.
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