Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder that is characterized by cutaneous findings, most notably café-au-lait spots and axillary freckling (see the images below), by skeletal dysplasias, and by the growth of both benign and malignant nervous system tumors, most notably benign neurofibromas.
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Café-au-lait spots in a 4-year-old boy.
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Axillary freckles.
Signs and symptoms
Signs and symptoms of NF1 can vary widely from patient to patient. The earliest clinical finding usually seen in children with NF1 is multiple café-au-lait spots. These may be present at birth or may appear over time, frequently increasing in size and number throughout childhood.
Axillary or inguinal freckles are rarely present at birth, but appear during childhood through adolescence. Subcutaneous or cutaneous neurofibromas are seen rarely in young children but appear over time in older children, adolescents, and adults.
Other signs and symptoms may include the following:
High blood pressure (potentially from renal artery stenosis or pheochromocytoma)
An international consensus revised the diagnostic citeria for NF1 in 2021.[1]
In the absence of a parent with NF1, the criteria for clinical diagnosis includes two or more of the following:
Six or more café-au-lait (CAL) macules greater than 5 mm in diameter in prepubertal children and greater than 15 mm postpubertal
Axillary or inguinal freckles (> 2 freckles) (if only CAL and freckling are present, one of these two cutaneous manifestations should be bilateral, and Legius syndrome should be considered, though the diagnosis is still likely NF1)
Two or more typical neurofibromas or one plexiform neurofibroma
Optic pathway glioma
Two or more iris hamartomas (Lisch nodules), often identified only through slit-lamp examination by an ophthalmologist; or two or more choroidal abnormalities (bright, patchy nodules imaged by optical adherence tomography/near infrared reflectance imaging)
Sphenoid dysplasia or typical long-bone abnormalities such as pseudarthrosis (exception is sphenoid dysplasia does not count as a separate criteria in the case of ipsilateral orbital plexiform neurofibroma)
Heterozygous pathogenic NF1 variant with a variant allele fraction of 50% in apparently normal tissue
In the presence of a parent with NF1, the criteria for clinical diagnosis include one of the above criteria.
See Workup for more detail.
Management
Medical care
There is no cure for neurofibromatosis. Patients should be routinely monitored for complications. Annual examinations should include the following:
Assessment of skin to look for new neurofibromas or progression of existing lesions
Check of blood pressure
Evaluation of growth and development
A complete eye exam
Evaluation of skeletal changes and abnormalities
Assessment of learning development
Chemotherapy, radiation therapy, or both may be used to treat cancerous tumors, but with the avoidance of radiation therapy when possible, due to the incurred increased risk of secondary malignancies.
Surgical care
Surgery can be used to remove tumors that cause pain or a loss of function. Neurofibromas that press on vital structures, obstruct vision, or grow rapidly deserve immediate attention.
Orthopedic intervention is indicated for rapidly progressive scoliosis and for some severe bony defects.
Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder that commonly is associated with cutaneous, neurologic, and orthopedic manifestations. It is the most frequent of the so-called hamartoses, conditions characterized by non-neoplastic tissue overgrowth.
NF1 is differentiated from central NF or NF type 2 in which patients demonstrate a relative paucity of cutaneous findings but have a high incidence of meningiomas and acoustic neuromas (which are frequently bilateral). NF1 has a lower incidence of central nervous system (CNS) tumors than NF2. However, complications of NF1 can include visual loss secondary to optic nerve gliomas, spinal cord tumors, scoliosis, vascular lesions, and long-bone abnormalities.
The manifestations of neurofibromatosis type 1 (NF1) result from a mutation in or deletion of the NF1 gene. The gene product neurofibromin serves as a tumor suppressor; decreased production of this protein results in the myriad of clinical features.
The estimated incidence of neurofibromatosis type 1 (NF1) is 1 in 3000, but the actual frequency may be higher because of less than complete ascertainment of mildly affected individuals. Approximately half of affected individuals represent first cases in the family as a result of a new genetic event or mutation.
Race-, sex-, and age-related demographics
All races and ethnic backgrounds are affected equally. However, evidence indicates that the risk for optic nerve glioma is lower in African Americans than in Caucasians and Hispanics.
Males and females are affected equally with this autosomal dominant condition. However, one study showed that female patients with NF1-associated optic glioma were twice as likely to undergo brain magnetic resonance imaging for visual symptoms and three times more likely to require treatment for visual decline than their male counterparts.[2]
Scoliosis may be especially severe in young girls compared to their male counterparts.
Although the genetic change causing NF1 is present at conception, clinical manifestations may appear slowly over many years.
Diagnosis often is made earlier in children born to an NF1-affected parent; the clinical criteria for diagnosis are fulfilled more easily, and the clinician may be more attuned to this possible diagnostic concern.
If an at-risk individual reaches the age of 10 years without meeting the diagnostic criteria for NF1, he or she is unlikely to be affected.
Life expectancy in neurofibromatosis type 1 (NF1) is approximately 8 years less than the general population.[3]
Lifetime risks for both benign and malignant tumors are increased in NF1-affected individuals.
Cutaneous or subcutaneous neurofibromas, optic nerve gliomas, dumbbell-shaped spinal cord tumors, and brain tumors, particularly gliomas, represent some of the well-recognized nerve-related neoplasms.
Adolescence for both genders may precipitate the development of subcutaneous and cutaneous neurofibromas. Increase in the size of existing neurofibromas and the appearance of new neurofibromas during pregnancy is a frequent observation in women with NF1.[4]
Plexiform neurofibromas, which are generally larger, more diffuse, and locally invasive, are seen in more than one fourth of patients with NF1[5] and can present difficult management decisions. The management of close surveillance versus intervention is often debated, with the recognition that complete resection of a plexiform neurofibroma without residual functional deficits is rarely possible. On the other hand, debulking or partial resection of plexiform neurofibromas may be undertaken for cosmetic purposes or if progressive functional consequences are anticipated.
Gliomas in patients with NF1 tend to be lower grade and have a more favorable prognosis than in patients without NF1, with pilocytic astrocytomas and low-grade astrocytomas (subtype intermediate) being most common.[6] However, diffusely infiltrating astrocytomas are also seen in a subset of patients and need to be managed accordingly.
Malignant peripheral nerve sheath tumors (MPNSTs) and neurosarcomas are not uncommon in adolescents and adults with NF1, with an approximate lifetime risk of 10%. These malignancies frequently arise from large plexiform neurofibromas or extensive peripheral nerve lesions. MPNSTs in patients with NF1 carry a poorer prognosis than in patients without this condition; tumor volume is an independent prognostic indicator.[7]
More than 1% of patients with NF1 develop an indolent symmetric sensory axonal neuropathy. However, some cases of polyneuropathy occur in association with diffuse nerve root lesions or MPNSTs.
Gastrointestinal stromal tumors (GIST), often multiple with a predilection for the proximal small bowel, may be seen in patients with NF1. Therefore, there should be a high index of suspicion for a GIST in a patient who presents with GI bleeding or intestinal obstruction.[8] Gene mutations typically seen in sporadic GISTs leading to malignant transformation are rarely identified in the GISTs removed from patients with NF1.[9] Instead, activation of the Ras-MAPK pathway and loss of heterozygosity of specific chromosomal regions may underlie the development of GISTs in patients with NF1.[10]
Learning disabilities with or without attention deficit hyperactivity disorder (ADHD) are seen in approximately 40% of NF1-affected individuals. A much smaller percentage experience more significant cognitive difficulties such as mild or moderate intellectual disability. Furthermore, a recent population based study reported a prevalence of autism spectrum disorder in 30%.[11]
Scoliosis in NF1 is often mild, but a subset of children younger than 10 years develop a more rapidly progressive form of scoliosis that requires aggressive intervention.
Bony abnormalities may be clinically silent, with radiographic evidence of long bone intramedullary fibrosis, cortical thinning, or vertebral dural ectasias often found incidentally. Sphenoid bone dysplasia and long-bone bowing or pseudarthrosis are common features of NF1. In the past, congenital tibial pseudarthrosis led to below-the-knee amputation; however, recent advances in orthopedic management with limb-sparing procedures have decreased the need for such drastic procedures.
Osteoporosis with statistically significant decreases in bone mineral density can be identified in individuals with NF1, perhaps even as early as childhood.[12] Whereas a number of metabolic pathways impacting bone metabolism have been implicated in the pathogenesis of bone abnormalities in people with NF, studies in children and teens with NF have provided evidence for increased rates of bone resorption as a likely cause for osteopenia.[13]
Emerging evidence shows that vitamin D deficiency combined with a higher than normal bone turnover contributes to decreased bone mineral density (BMD) in patients with NF1.[14] One study looking at adults with NF1 (mean age, early 40s), showed that 50% had osteopenia and 19% had frank osteoporosis. Males were more likely than females to have reduced BMD; 56% of patients had a low 25-hydroxy-vitamin D while 34% had elevated parathyroid hormone.[15] Judicious vitamin D supplementation may prove beneficial for patients with NF1 who have vitamin D deficiency or evidence of osteopenia.
Hypertension in NF1 can be seen at any age, with many adults with NF1 manifesting the usual essential form of hypertension. However, any person with NF1 and high blood pressure must be evaluated carefully for 2 alternative causes of hypertension (see Prognosis).
Pheochromocytomas are not rare (< 5%) in NF1 and can cause severe, fluctuating hypertension.
Vascular stenosis (ie, renal artery stenosis secondary to fibromuscular dysplasia) also may result in hypertension that may not respond well to standard pharmacologic management.
Other vascular lesions, especially in the central nervous system, such as vascular ectasias, stenoses, moyamoya disease, and aneurysms, occur more frequently in patients with NF1. Rarely, coronary artery aneurysms are identified in symptomatic or even asymptomatic individuals with NF1.[16]
Short stature is common in NF1; affected individuals are often shorter than their unaffected siblings.
Macrocephaly is common in NF1 and should not cause undo alarm if present in affected infants or young children, unless serial head circumference measurements confirm the rapid crossing of percentiles.
Chiari type 1 malformations are seen with increased frequency in the NF1 population.
Puberty usually occurs at a normal age, but precocious puberty with growth acceleration may occur in a small number of individuals. When precocious puberty is present, the patient must be evaluated for a chiasmal lesion causing disruption of the hypothalamic-pituitary axis.
Although most individuals with neurofibromatosis type 1 (NF1) lead relatively long and healthy lives, the overall life expectancy may be reduced by on average 8 years. The major causes for this increased morbidity and subsequent mortality are hypertension, sequelae of spinal cord lesions, and malignancy.
Prompt attention to complications of NF1 and early detection of medical problems may significantly reduce the overall morbidity and mortality rates.
Patients and their families may be referred to NF-specific national and regional support groups for continuous updates on treatment advances and for emotional support.
Inform patients of symptoms that would require immediate medical attention, including headaches increasing in intensity or frequency or focal neurological deficits.
In the absence of a parent with neurofibromatosis type 1 (NF1), the criteria for clinical diagnosis[1] includes two or more of the following:
Six or more café-au-lait (CAL) macules greater than 5 mm in diameter in prepubertal children and greater than 15 mm postpubertal
Axillary or inguinal freckles (> 2 freckles) (if only CAL and freckling are present, one of these two cutaneous manifestations should be bilateral, and Legius syndrome should be considered, though the diagnosis is still likely NF1)
Two or more typical neurofibromas or one plexiform neurofibroma
Optic pathway glioma
Two or more iris hamartomas (Lisch nodules), often identified only through slit-lamp examination by an ophthalmologist; or two or more choroidal abnormalities (bright, patchy nodules imaged by optical adherence tomography/near infrared reflectance imaging)
Sphenoid dysplasia or typical long-bone abnormalities such as pseudarthrosis (exception is sphenoid dysplasia does not count as a separate criteria in the case of ipsilateral orbital plexiform neurofibroma)
Heterozygous pathogenic NF1 variant with a variant allele fraction of 50% in apparently normal tissue
In the presence of a parent with NF1, the criteria for clinical diagnosis include one of the above criteria.
The earliest clinical finding usually seen in children with neurofibromatosis type 1 (NF1) is multiple café-au-lait spots. These may be present at birth or may appear over time, frequently increasing in size and number throughout childhood (See the image below).
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Café-au-lait spots in a 4-year-old boy.
In adults, café-au-lait spots tend to fade and may be less obvious on clinical examination.
Axillary or inguinal freckles are rarely present at birth, but appear during childhood through adolescence (See the images below).
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Axillary freckles.
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Inguinal freckles.
Subcutaneous or cutaneous neurofibromas are seen rarely in young children but appear over time in older children, adolescents, and adults (See the image below).
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Multiple neurofibromas in a 28-year-old man.
Deep lesions may be detected only through palpation, whereas cutaneous lesions may appear initially as small papules on the trunk, extremities, scalp, or face.
Puberty or pregnancy may be associated with an increased number of neurofibromas as well as more rapid growth of preexisting lesions.
Plexiform neurofibromas are more diffuse growths that can be locally invasive and quite deep; they may be associated with bony erosion and pain (See the image below).
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Plexiform neurofibroma of the right thigh.
Plexiform neurofibromas also may be accompanied by overlying hyperpigmentation or hypertrichosis.
Rarely, rapid growth of a neurofibroma may occur and can be suggestive of malignant transformation.
Optic pathway tumors, typically histologically low-grade pilocytic astrocytomas, occur in 15-20%. They may be clinically silent, but can be symptomatic in 30-50%, primarily in children younger than 6 years.[17] Gender may be a major prognostic factor, as females have been reported to have a three-fold risk to require treatment for visual decline than males.[2]
Asymmetric, noncorrectable visual loss is the most common presenting symptom, but subtle peripheral field defects, color discrimination difficulties, optic nerve pallor, or proptosis may occur without visual acuity problems.
Some older children and adolescents may present with worsening vision secondary to a slow-growing optic nerve glioma (ONG) and, therefore, monitoring for visual difficulties should continue throughout childhood and adulthood. Adults may have a visually insignificant optic nerve glioma detected incidentally on a head imaging study.
Posterior optic pathway tumors with hypothalamic encroachment may present as precocious puberty.
Although Lisch nodules occasionally can be seen with a direct or indirect ophthalmoscope, especially in individuals with light-colored irides, they are usually not readily visible without using a slit lamp (See the image below).
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Lisch nodules.
Choroidal abnormalities with a patchy appearance may also be noted on funduscopic examination using infrared monochromatic light. Retinal corkscrew vascular changes have also been described in some patients with NF1.
Sphenoid bone dysplasia is usually asymptomatic, but occasionally can be associated with herniation through the bony defect. In the occasional patient with a plexiform neurofibroma of the eyelid, ipsilateral sphenoid dysplasia is frequently present.
Congenital pseudarthrosis may be evident at birth, with bowing of the tibia being the most typical presentation (See the image below).
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Radial and ulnar bowing and obliteration of the intramedullary spaces.
Thinning and angulation of long bones can occur throughout early childhood and adolescence, with prominence of the anterior tibia and progressive deformity. Less commonly, bowing of the forearm can occur.
Scoliosis with or without kyphosis may become evident in childhood or adolescence. When found in a child younger than 10 years, it is associated with a much poorer prognosis and is likely to progress rapidly. Scoliosis detected during adolescence still should be monitored clinically, but is much less likely to require orthopedic intervention.
Blood pressure should be checked during every clinical visit because of the distinct possibility of alternative causes of hypertension in NF1.
Head circumference should be monitored throughout the first 3 years of life, as with any child. Relative macrocephaly should not cause alarm, unless serial measurements suggest rapid growth with crossing of 2 or more percentile lines.
Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by decreased production of the protein neurofibromin, which has a putative tumor suppressor function. Only one NF1 gene needs be deleted or mutated to produce the condition.
The NF1 gene has been localized to the long arm of chromosome 17. Although more than 3,000 NF1 pathogenic variants have been identified, only four consistent genotype-phenotyp correlations have been reported, relevent to only 10–15% of NF1 patients.[18]
The precise role of neurofibromin is not fully understood, but the multitude of clinical effects suggests that this gene product has diverse functions in various tissues.
Mutations in another gene (SPRED1) have been identified in a subset of patients described to have an NF-like syndrome, also known as Legius syndrome.[19] Individuals with a SPRED1 mutation may be incorrectly diagnosed with NF1 based on the presence of multiple café-au-lait spots and axillary or inguinal freckles, but these patients do not go on to develop the neurofibromas or Lisch nodules that are found in most adults with true NF1.
The diagnosis of neurofibromatosis type 1 (NF1) is usually made clinically, however, molecular testing may be helpful for younger patients with a single clinical finding, such as multiple café-au-lait spots in the absence of a positive family history.
Sequencing of the neurofibromin gene offers the highest detection rate and may approach 95% in clinically affected individuals.
97% of patients with NF1 are expected to meet clinical diagnosis by the age of 8 years. For those not meeting clinical criteria or for those that overlap with Legius Syndrome, molecular testing can be useful for confirmation.[20]
Legius Syndrome should be suspected in patients with macrocephaly, café-au-lait spots and axillary freckling and no NF1 tumors (neurofibromas, lisch nodules, optic gliomas or plexiform neurofibromas). Given that NF1 is more common, testing should start with NF1 sequencing and reflex to SPRED1 if negative.
Neurofibromatosis type 1 (NF1) may be diagnosed by either of two methods during the prenatal period.
In a family with multiple affected members, linkage analysis can track the NF1 gene through the generations to determine which chromosome 17 region the fetus received. However, with advances in molecular diagnosis, family studies are rarely necessary.
For a parent with NF1 who is the only affected family member, gene sequencing can be used to identify a specific gene mutation. Identification of the mutation in the affected parent would permit prenatal diagnosis via amniocentesis or chorionic villus sample (CVS).
When a specific mutation is known, preimplantation genetic diagnosis can also be offered to couples using in vitro fertilization with selection of unaffected embryos for transfer.
Urinary free catecholamines (norepinephrine and epinephrine) as well as their metabolites (normetanephrine, metanephrine and vanillyl-mandelic acid) measured on a 24-hour urine collection are good biochemical screening tests for a suspected pheochromocytoma.[21]
Plasma catecholamines may also be measured using liquid chromatography. Measurement of free plasma metanephrine is more sensitive in detection of a pheochromocytoma than plasma catecholamines.[22]
Plain films may detect a variety of subtle and not so subtle bony abnormalities associated with neurofibromatosis type 1 (NF1). See the image below.
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Radial and ulnar bowing and obliteration of the intramedullary spaces.
Radiographs should be obtained when clinical findings suggest possible modeling defects of the long bones or ribs, possible bony erosion secondary to an adjacent plexiform neurofibroma, signs of scoliosis, or bone pain.
MRI or CT scan
The use of routine screening brain neuroimaging in patients with NF1 is controversial. This is mainly due to the lack of consistent evidence that early detection reduces the rate of vision loss and that identifying and repeating interval imaging of asymptomatic optic pathway gliomas that never progress exposes young children to repeated sedations.[17] However, there is emerging evidence that early radiological identification prior to the development of vision loss may lead to improved future visual outcomes.[23] Furthermore, a negative MRI at a young age may predict the lack of the development of symptomatic optic nerve gliomas in the future.[23]
Some clinicians prefer to perform a baseline CT scan or MRI in children or adults at the time of diagnosis, subsequently recommending another imaging study only if neurological problems arise. Other clinicians feel that baseline studies are of limited value, since detecting an asymptomatic optic nerve glioma would probably not prompt medical intervention.
MRI is the preferred diagnostic head imaging study in NF1.
MRI has been shown to frequently detect unidentified bright objects (UBOs) in the brain parenchyma of patients with NF1. See the image below.
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Unidentified bright object (UBO) within the brain parenchyma.
These bright spots seen on T2-weighted images generally do not enhance, cause no mass effect, have indistinct borders, and often resolve as the individual gets older. They are more frequently located in the cerebellar white matter, medial temporal lobe, and thalamus, and tend to be bilateral.[24]
They are believed to represent benign hamartomas in NF1 and, in some reports, are seen more often in children with NF1-related learning disabilities.
However, T2 hyperintensities can also represent nonoptic pathway tumors.[25, 24] Probable tumors can develop in half of children, and can progress radiographically, with nearly a third requiring treatment, thus requiring clinical and radiographic surveillance. Nonoptic pathway tumors are more frequently located within the globus pallidus and medulla.
Brain CT scan or MRI should be considered to evaluate ventricular size when increasing head circumferences is noted in an infant or young child. Rarely, hydrocephalus and/or a Chiari type 1 malformation are seen in children and even adults with NF1.
MRI is also a valuable tool in evaluating the optic nerves or optic chiasm. See the image below.
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Left optic nerve glioma with thickening of the nerve and proptosis.
See the list below:
It is indicated for patients with optic nerve pallor, visual changes, proptosis, or precocious puberty.
Thin cuts through the orbits and optic nerves are an ideal way to identify subtle optic nerve pathology.
Brain MRI should be considered in patients with headaches that are changing in quality or are increasing in frequency or intensity.
MRI has proven useful in evaluating internal lesions such as mediastinal masses, spinal cord tumors, deep plexiform neurofibromas, neurofibromas of the brachial or sacral plexus, and abdominopelvic lesions. Short T1-inversion recovery MR images can be used to accurately estimate the volume of a plexiform neurofibroma, which can be useful for both diagnosis and follow-up. In adults, unlike children where continued growth of plexiform lesions is quite common, rapid growth of a plexiform neurofibroma may portend malignant transformation.[26] Although MRI is not always helpful in differentiating benign peripheral nerve lesions from malignant lesions, central hypointense areas within a lesion noted on T2-weighted images (the so-called target sign) is more suggestive of a benign lesion.[27] On the other hand, MRI evidence of intratumoral lobulation or T1 high signal intensity are much more suggestive of malignancy.[28]
CT and MRI are first-line imaging studies when pheochromocytoma is suspected based on abnormal serum or urine screening tests.[21] If CT or MRI is unable to identify the suspected pheochromocytoma, then metaiodobenzylguanidine (MIBG) scintigraphy is indicated.[29]
Positron emission tomography: F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) may be used to stage and follow up MPNSTs before, during, and after therapy.[30]
Gallium-67 scintigraphy may be used as a screening tool for patients with NF, especially patients with a large plexiform neurofibroma when there is concern about 1 or more areas having undergone malignant transformation.[31]
Electroencephalogram (EEG) is indicated in patients with symptoms suggestive of seizures. Seizures are reported more often in patients with neurofibromatosis type 1 (NF1) than in the general population, occurring in between 4 and 7%.
Polysomnogram should be considered in patients with sleep-disordered breathing, as the prevalence of obstructed sleep apnea appears to be high, more than 50% in one series.[32]
MRI alone is generally sufficient for medical and/or surgical decision making. Occasionally, myelography is needed to clarify the extent of a spinal cord tumor.
Slit-lamp examination by an experienced ophthalmologist can provide key diagnostic information in older children and adults who have only a single clinical criterion such as multiple café-au-lait spots.
The occurrence of Lisch nodules appears to be age dependent; more than 95% of NF1-affected individuals older than 10 years have this iris finding.
This examination is invaluable in determining if parents of an affected child carry the NF1 mutation, even when the parent has no other signs of the condition.
Neurofibromas are generally well-differentiated tumors that contain elongated spindle-shaped cells as well as pleomorphic fibroblast-like cells. Rarely, inflammatory cells may be seen in these otherwise benign-appearing lesions.
Optic gliomas also are indolent, generally very low-grade lesions. In fact, optic nerve lesions associated with NF1 are less aggressive and respond more favorably to current therapies than optic nerve tumors in the general population.
Occasionally, a neurofibroma (typically large or deep plexiform neurofibroma or peripheral nerve sheath tumor residing within the brachial or pelvic plexus) undergoes malignant transformation to a neurofibrosarcoma. Unlike benign neurofibromas, neurofibrosarcomas are characteristically hypercellular with giant cells, increased numbers of mitoses, and vascular proliferation.
Because collections of malignant cells may be present between larger masses of benign cells in a plexiform neurofibroma, examining a plexiform tumor carefully (ie, taking samples from multiple regions to confirm that it is indeed benign) is essential.
Although patients with neurofibromatosis type 1 (NF1) can be cared for in the primary care setting, additional medical concerns need to be addressed on a routine basis.
An outline of reasonable guidelines in caring for patients with NF1 is as follows:
Annual examinations should focus on potential complications of NF. Each examination should include blood pressure measurement, assessment of the skin for typical lesions (including early or growing neurofibromas), visual acuity check, evaluation of the eyes for evidence of proptosis or strabismus, and examination of the spine and extremities for any abnormalities. Neurologic evaluation should include a careful history for headaches or motor or sensory symptoms as well as a comprehensive motor and sensory examination.
Annual ophthalmologic examinations should check for optic nerve pallor, visual acuity changes, visual field defects, and Lisch nodules. Patients should be referred to an ophthalmologist promptly if the treating physician has any concerns about visual acuity, evidence of proptosis, or a palpebral plexiform neurofibroma obstructing vision.
Hospitalization may be necessary for major surgical procedures and workup of uncontrolled hypertension.
Many minor surgical procedures (eg, removal of cutaneous neurofibromas) may be done in an outpatient surgical setting.
For individuals diagnosed with neurofibromatosis type 1 (NF1), routine examinations should focus on the potential complications.
Annual examinations permit early detection of problems, decreasing morbidity and improving quality of life.
Annual eye examinations are important in early detection of optic nerve lesions.
Cutaneous examination performed at each visit should look for new neurofibromas or progression of preexisting lesions. Plexiform neurofibromas may be locally invasive, therefore clinical evaluation should be directed at determining the extent of involvement and detecting evidence of bony erosion or nerve entrapment.
Skeletal involvement, including scoliosis, hemihypertrophy, or long-bone modeling defects, should be documented.
Blood pressure should be checked at each visit and hypertension treated promptly if detected. Hypertension workup should include evaluation for pheochromocytoma (ie, measurement of urinary catecholamines and metanephrines) and testing for renal artery stenosis. Percutaneous transluminal renal artery angioplasty may, in some cases, effectively treat renal artery stenosis secondary to fibromuscular dysplasia.
Interval history should focus on subtle sensory or motor symptoms such as paresthesia, radiculopathy, weakness, or muscle atrophy.
Patients should be asked about incontinence. At each visit, minor changes in the sensory or motor examination should be documented carefully.
Symptoms of spinal cord neurofibromas may be subtle and slowly progressive; prompt identification and early surgical intervention allow for optimal outcome.
Removal of neurofibromas for medical or cosmetic indications is one of the most common procedures on individuals with NF1.
Recent advances in laser technology have permitted nonsurgical removal of small, cutaneous neurofibromas.
However, careful surgical resection of small or large neurofibromas may leave an even smaller, less prominent scar.
Although laser treatment has been used for various cutaneous, hyperpigmented lesions (eg, port-wine stains, tattoos), it has not yet proven successful in permanent removal of café-au-lait spots.
Both selumetinib and mirdametinib are MEK inhibitors approved for the treatment of symptomatic plexiform neurofibromas in patients with NF1 who are not eligible for complete surgical removal.[33, 34]
The use of chemotherapy, especially with carboplatin and vincristine have been shown to be effective in controlling the progression of optic nerve gliomas.
Surgical resection of neurofibromas can be accomplished, but plastic surgery consultation is advisable for areas of great cosmetic concern such as the face. Resection is the treatment of choice for pheochromocytomas.[35]
Neurofibromas that press on vital structures, obstruct vision, or grow rapidly deserve immediate attention.
Plexiform neurofibromas may be difficult to approach surgically, often recurring after resection because of residual tumor cell collections deep in soft tissues. Surgeons must realize that removing some of these lesions can result in substantial blood loss and must plan accordingly.
Symptomatic peripheral nerve sheath tumors located along the nerves of the brachial or pelvic plexus sometimes require surgical intervention with the very real potential for postoperative nerve dysfunction. Added to this is the risk for malignant transformation that carries with it a very poor prognosis; the decision to operate requires much thought and careful consideration. One should always weigh the potential diagnostic benefits taking into account one's index of suspicion for malignancy, against the potential risks for long-term neurologic sequelae.
For many patients, neurofibromas on the scalp, along the hairline, or around the waist where clothes rub can cause great irritation and discomfort. Therefore, removing these should not be considered cosmetic but a necessary medical procedure.
Resection of spinal cord tumors is difficult but often necessary to prevent progressive paraplegia or quadriplegia.
Acting promptly when neurological symptoms appear is important to maximize operative success.
Surgical intervention may not guarantee a complete resection of the tumor, but it may serve a palliative function in some cases.
Single fraction radiosurgery has been used in some centers to treat benign intradural extramedullary spinal cord tumors. This technique may be used as a primary therapeutic approach or in cases of postsurgical progression or when residual tumor is a concern after a subtotal surgical resection.[36]
Orthopedic intervention is indicated for rapidly progressive scoliosis and for some severe bony defects.
Following patients with NF1 when scoliosis is first detected is advisable, so that nonsurgical approaches may be used in an attempt to obviate the need for a future spinal fusion procedure.
Limb-sparing procedures in addition to new bracing and casting technologies have decreased the need for amputation in patients with a pseudarthrosis. See the image below.
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Below-the-knee amputation for tibial pseudarthrosis.
Patients with long-bone defects are best served by ongoing orthopedic care.
Some hypertensive patients with renal artery stenosis require surgical resection and repair instead of or following angioplasty.
Resection of a pheochromocytoma requires preoperative treatment with an alpha-blocker (preferably a selective postsynaptic alpha1-receptor antagonist) to offset the effects of catecholamine release during surgical manipulation of the tumor.[37]
The neurologist serves as a key consultant and provides valuable information concerning changes in neurological status by performing a complete, focused examination.
The neurosurgeon serves as an expert consultant when a spinal cord or brain tumor is identified and works closely with the neurologist to determine the optimal timing and best surgical approach on an individual basis.
The ophthalmologist serves as a valuable member of the NF1 consultation team, evaluating patients on an annual basis for changes in visual acuity, field defects, or appearance of Lisch nodules.
The geneticist provides information concerning diagnosis, diagnostic testing, inheritance, and risks for recurrence in future children. Family planning options and prenatal diagnosis may be addressed in this clinical setting.
The orthopedist is a key consultant for the many NF1-related bone abnormalities (eg, scoliosis, pseudarthrosis, hemihypertrophy, bony erosion by plexiform neurofibromas).
The developmental pediatrician may be an invaluable resource in evaluating a child with NF1 and learning disabilities, attention deficit hyperactivity disorder, or autism spectrum disorder.
In addition to these most frequently used consultants, patients may need to see others for specific NF1 concerns. Examples include the following:
A nephrologist to help rule out renal vascular lesions
A general or plastic surgeon to consider removal of neurofibromas
An oncologist to manage and treat symptomatic optic nerve gliomas, brain tumors, neurosarcomas and MPNSTs
An otolaryngologist for suspected hearing loss or an acoustic nerve lesion
A dermatologist to assess cutaneous lesions
An oculoplastic surgeon for an orbital plexiform neurofibroma
No activity restrictions are necessary, except for an individual with specific orthopedic concerns (as recommended by the consulting surgeon).
Patients with spinal fusion procedures as well as individuals with significant long-bone weakness or pseudarthrosis may need to limit certain athletic activities.
Patients with neurological sequelae from spinal cord lesions may be restricted in their activities secondary to physical disabilities.
The following organizations have released guidelines for the management of neurofibromatosis type 1 (NF1). Key diagnostic and treatment recommendations have been reviewed and integrated throughout the article.
(2018) American College of Medical Genetics and Genomics (ACMG) - Care of adults with neurofibromatosis type 1[38]
(2017) American Association of Cancer Research (AACR) - Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 1[39]
(2007) Nerve Tumours UK - Guidelines for the diagnosis and management of individuals with neurofibromatosis 1[40]
No known medical therapies are curative or preventive for patients with neurofibromatosis type 1 (NF1). However, the development and FDA approval of selumetinib provides hope for further understanding and new drug development. Several drug trials continue to seek medications that slow or halt the growth of tumors associated with NF1.
For a small subset of patients with pruritus due to cutaneous neurofibromas, diphenhydramine may provide some temporary relief. Such patients also are encouraged to avoid hot showers and baths, since hot temperatures may exacerbate itching.
Treatment with carboplatin shows efficacy in controlling the growth of visually significant optic gliomas.
Clinical Context:
First-generation antihistamine with anticholinergic effects that binds to H1 receptors in the CNS and the body.
Competitively blocks histamine from binding to H1 receptors. Has significant antimuscarinic activity and penetrates CNS, which causes pronounced tendency to induce sedation.
Approximately half of those treated with conventional doses experience some degree of somnolence. A small percentage of children paradoxically respond to diphenhydramine with agitation.
For symptomatic relief of pruritus caused by release of histamine in inflammatory reactions.
Clinical Context:
Alkylating agent that has been used extensively in treatment of ovarian cancer, but with efficacy in treatment of optic nerve lesions in combination with vincristine sulfate.
Clinical Context:
Selumetinib is an inhibitor of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2). MEK1/2 proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. Both MEK and ERK are critical components of the RAS-regulated RAF-MEK-ERK pathway, which is often activated in different types of cancers. It is indicated for the treatment of NF1 in children and adolescents aged ≥2 years who have symptomatic, inoperable PN.
What is neurofibromatosis type 1 (NF1)?What are the signs and symptoms of neurofibromatosis type 1 (NF1)?What are the diagnostic criteria for neurofibromatosis type 1 (NF1)?What is involved in the monitoring of patients with neurofibromatosis type 1 (NF1)?What is the role of surgery in the management of neurofibromatosis type 1 (NF1)?How is neurofibromatosis type 1 (NF1) differentiated from central neurofibromatosis or neurofibromatosis type 2 (NF2)?What is the pathophysiology of neurofibromatosis type 1 (NF1)?What is the life expectancy of patients with neurofibromatosis type 1 (NF1)?Which nerve-related neoplasms are associated with neurofibromatosis type 1 (NF1)?Which factors may precipitate the development of subcutaneous and cutaneous neurofibromas?How prevalent are plexiform neurofibromas in neurofibromatosis type 1 (NF1)?What is the prognosis of gliomas in neurofibromatosis type 1 (NF1)?What is the prognosis of malignant peripheral nerve sheath tumors (MPNSTs) and neurosarcomas in neurofibromatosis type 1 (NF1)?What is the prevalence of sensory axonal neuropathy in neurofibromatosis type 1 (NF1)?What are the signs of GI stromal tumors (GIST) in neurofibromatosis type 1 (NF1)?What is the prevalence of learning disabilities in patients with neurofibromatosis type 1 (NF1)?What is the skeletal morbidity of neurofibromatosis type 1 (NF1)?What are the manifestations of hypertension in neurofibromatosis type 1 (NF1)?What types of vascular lesions occur in patients with neurofibromatosis type 1 (NF1)?What are common complications of neurofibromatosis type 1 (NF1)?What are the racial predilections for neurofibromatosis type 1 (NF1)?How does the incidence of neurofibromatosis type 1 (NF1) vary by sex?At what age is neurofibromatosis type 1 (NF1) typically diagnosed?What is the incidence of neurofibromatosis type 1 (NF1)?What are the clinical criteria used to diagnose neurofibromatosis type 1 (NF1)?What are physical findings characteristic of neurofibromatosis type 1 (NF1)?What are the physical findings of subcutaneous or cutaneous neurofibromas characteristic of neurofibromatosis type 1 (NF1)?Which physical findings of neurofibromatosis type 1 (NF1) are associated with puberty or pregnancy?Which physical findings are characteristics of plexiform neurofibromas in neurofibromatosis type 1 (NF1)?What are physical findings of optic pathway tumors characteristic of neurofibromatosis type 1 (NF1)?What are physical findings of bone abnormalities characteristic of neurofibromatosis type 1 (NF1)?What should be included in regular clinical visits for patients with neurofibromatosis type 1 (NF1)?What causes neurofibromatosis type 1 (NF1)?What conditions should be included in the differential diagnosis of neurofibromatosis type 1 (NF1)?What are the differential diagnoses for Neurofibromatosis Type 1?What is the role of lab studies in the workup of neurofibromatosis type 1 (NF1)?Which findings in the evaluation of neurofibromatosis type 1 (NF1) should raise suspicion of Legius syndrome?How is neurofibromatosis type 1 (NF1) diagnosed prenatally?What is the role of urine analysis in the workup of neurofibromatosis type 1 (NF1)?What is the role of radiography in the workup of neurofibromatosis type 1 (NF1)?What is the role of MRI or CT scan in routine screening of patients with neurofibromatosis type 1 (NF1)?What are the advantages of MRI for the diagnosis of neurofibromatosis type 1 (NF1)?What are the indications for MRI and CT scan in the workup of neurofibromatosis type 1 (NF1)?What is the role of electroencephalogram (EEG) in the workup of neurofibromatosis type 1 (NF1)?What is the role of a slit lamp exam in the evaluation of neurofibromatosis type 1 (NF1)?Which histologic findings are characteristic of neurofibromatosis type 1 (NF1)?What is the focus of routine exams for patients with neurofibromatosis type 1 (NF1)?What should be the focus of interval history in patients with neurofibromatosis type 1 (NF1)?What are the options for removal of neurofibromas in neurofibromatosis type 1 (NF1)?What is the role of laser treatment for neurofibromatosis type 1 (NF1)?What is the role of chemotherapy in the treatment of neurofibromatosis type 1 (NF1)?What is the role of surgery in the treatment of neurofibromatosis type 1 (NF1)?When is resection of spinal cord tumors indicated in neurofibromatosis type 1 (NF1)?When is orthopedic intervention indicated in the treatment of neurofibromatosis type 1 (NF1)?What are the indications for surgical resection in the treatment of neurofibromatosis type 1 (NF1)?Which specialist consultations are needed for the treatment of neurofibromatosis type 1 (NF1)?Which specialist consultations are needed to address specific concerns in neurofibromatosis type 1 (NF1)?Which activity modifications are used in the treatment of neurofibromatosis type 1 (NF1)?What is the role of drug treatment for neurofibromatosis type 1 (NF1)?Which medications in the drug class Antineoplastic agents are used in the treatment of Neurofibromatosis Type 1?Which medications in the drug class Antihistamines are used in the treatment of Neurofibromatosis Type 1?
David T Hsieh, MD, FAAP, Professor of Pediatrics and Neurology, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine
Disclosure: Nothing to disclose.
Coauthor(s)
Luis O Rohena, MD, PhD, FAAP, FACMG, Deputy Chief, Department of Pediatrics, Chief, Medical Genetics, San Antonio Military Medical Center; Associate Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Associate Professor of Pediatrics, University of Texas Health Science Center at San Antonio
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
George I Jallo, MD, Professor of Neurosurgery, Pediatrics, and Oncology, Director, Clinical Pediatric Neurosurgery, Department of Neurosurgery, Johns Hopkins University School of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Ann M Neumeyer, MD, Medical Director, Lurie Center for Autism; Assistant Professor of Neurology, Harvard Medical School; Child Neurologist, Massachusetts General Hospital
Disclosure: Nothing to disclose.
Acknowledgements
The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, the Department of the Air Force, Department of Defense or the U.S. Government.
Beth A Pletcher, MD Associate Professor, Co-Director of The Neurofibromatosis Center of New Jersey, Department of Pediatrics, University of Medicine and Dentistry of New Jersey
Beth A Pletcher, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Medical Association, and American Society of Human Genetics
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