Version May 2024
INTRODUCTION — There are several clinically and genetically distinct forms of neurofibromatosis: neurofibromatosis type 1, NF2-related schwannomatosis (NF2, formerly neurofibromatosis type 2), and schwannomatoses related to genetic variants other than NF2. NF1, previously known as von Recklinghausen disease, is the most common type. The hallmarks of NF1 are multiple café-au-lait macules and 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 variant in the neurofibromin 1 (NF1) gene.
The pathogenesis, clinical features, and diagnosis of NF1 are reviewed here. Management and prognosis are discussed separately (see "Neurofibromatosis type 1 (NF1): Management and prognosis"). The other two forms of neurofibromatosis, NF2 and schwannomatosis, are also discussed in detail separately. (See "NF2-related schwannomatosis (formerly neurofibromatosis type 2)" and "Schwannomatoses related to genetic variants other than NF2".)
EPIDEMIOLOGY — NF1 is an autosomal dominant genetic disorder with an incidence of approximately 1:2600 to 1:3000 individuals [1]. Approximately one-half of the cases are familial (inherited) [1]. The de novo mutations occur primarily in paternally derived chromosomes [2]. The incidence of segmental NF1 is unknown, but the prevalence is estimated at 1:36,000 to 1:40,000 [3]. A study of death certificates in the United States revealed a mean age at death for persons with NF1 of 54.4 years and median of 59 years, well below population norms (70.1 and 74 years, respectively) [4]. Malignant tumors and vascular disease were significantly overrepresented among those with NF1 who had died at an age <40 years. A population-based study in Finland revealed an overall prevalence of NF1 of approximately 1:4000, but the prevalence decreased with age, with a hazard ratio of death among individuals with NF1 of 3.10 [5].
PATHOGENESIS — NF1 is due to pathogenic variants in the NF1 gene, located at chromosome 17q11.2 [6]. The protein product, neurofibromin, belongs to a family of guanosine triphosphate hydrolase (GTPase)-activating proteins (GAPs) that stimulate intrinsic GTPase activity in the ras p21 family (21 kD rat sarcoma viral oncogene homologs). Ras activates a number of signaling pathways that include the stem cell factor (SCF)/c-kit signaling, mammalian (mechanistic) target of rapamycin (mTOR), and mitogen-activated protein kinase (MAPK) pathways.
Pathogenic variants in the NF1 gene result in loss of production or reduced function of protein, causing the wide spectrum of clinical findings, including NF1-associated tumors [7]. Penetrance, or the likelihood that the individual carrying the variant will manifest the disorder, is complete. NF1 is highly variable in its expression, however (ie, the severity of and specific manifestations of the disorder vary among affected individuals within the same family and from one family to another) [8]. Somatic mutation or loss of heterozygosity at the NF1 locus, in combination with a germline NF1 mutation, leads to complete loss of neurofibromin expression that is seen in NF1 lesions such as pseudoarthrosis [9] and neurofibromas [10]. NF1 therefore functions as a tumor suppressor gene. It is possible that haploinsufficiency (ie, heterozygosity for a pathogenic variant with an intact second allele) accounts for some aspects of the phenotype, such as neurocognitive problems.
Segmental NF1 is caused by somatic mosaicism due to a postzygotic mutation in the NF1 gene [11]. This results in some cells having two fully functional NF1 genes and other cells containing a pathogenic variant in one copy of the NF1 gene. Persons with segmental NF1 do not have an affected parent. When an adult with localized NF1 who has mosaicism within both somatic and gonadal tissues transmits the mutation to a child, this offspring will carry the NF1 mutation in all cells and will not have segmental manifestations. Rare individuals have been described who have only germline mosaicism without apparent somatic features [12,13].
CLINICAL MANIFESTATIONS — The typical order of appearance of clinical manifestations is café-au-lait macules, axillary and/or inguinal freckling, Lisch nodules (iris hamartomas), and neurofibromas [14]. Osseous dysplasias, if present, usually appear during the patient's first year after birth, and symptomatic optic pathway glioma (OPG) usually occurs by the time the patient is three years of age (table 1). Other tumors and neurologic complications typically begin to appear after the first year of life. Hypertension may occur in childhood. Malignant transformation of tumors may also occur in childhood but more often occurs in adolescence and adulthood.
Café-au-lait macules — Café-au-lait macules are flat, uniformly hyperpigmented macules that appear during the first year after birth and usually increase in number during early childhood (picture 1). The number of café-au-lait macules then stabilizes over time. Up to 15 percent of the general population has one to three café-au-lait macules; however, the presence of six or more café-au-lait macules is highly suggestive of NF1 [15,16]. One retrospective study used age and number/type of café-au-lait macules at the time of presentation to determine the risk of having NF1 [17]. Younger age at presentation (≤29 months) and presence of six or more café-au-lait macules was associated with a high risk of having NF1 (80.4 percent, 95% CI 74.6-86.2 percent) compared with age >29 months and fewer than six café-au-lait macules or at least one atypical café-au-lait macule (0.9 percent, 95% CI 0-2.6 percent). (See "Benign pigmented skin lesions other than melanocytic nevi (moles)", section on 'Café-au-lait macule' and 'Diagnosis' below.)
Approximately 95 percent of adults with NF1 have café-au-lait macules, but they tend to fade later in life and may be difficult to distinguish in older individuals. A Wood's lamp can be useful to visualize these macules when they are not readily discernible by gross inspection [18], although the diagnostic criteria specify examination in ordinary room lighting. (See "Office-based dermatologic diagnostic procedures", section on 'Wood's lamp examination (black light)'.)
Freckling — Freckling in the axillary or inguinal regions (Crowe sign) is a diagnostic criterion distinct from café-au-lait macules. The freckles are smaller in size than café-au-lait macules, appear later, and usually occur in clusters in skin folds rather than randomly (picture 2 and picture 3).
Freckling occurs mostly in regions of skin apposition, especially the axillary and inguinal areas. Freckling usually is not apparent at birth but often appears by age three to five years, typically first in the inguinal region [15]. Freckling may also occur in other intertriginous areas, such as the neckline or inframammary areas in women. In some individuals, freckling may occur elsewhere on the body and may be diffuse. One or two small freckles or the presence of a café-au-lait macule in a skin fold does not fulfill the diagnostic criterion for skin fold freckling.
Lisch nodules — Lisch nodules are raised, tan-colored hamartomas of the iris and represent a specific finding for NF1. They do not affect vision in any manner. Lisch nodules are useful both in establishing a diagnosis of NF1 in a child and in determining whether a parent is affected. These lesions are detected in fewer than 10 percent of affected children younger than six years of age but are seen in greater than 90 percent of adults [19,20]. They may be seen with a direct ophthalmoscope if the nodules are large or numerous and the iris is light in color, but the slit lamp is a more reliable way to distinguish Lisch nodules from iris nevi, which are not associated with NF1 (picture 4) [21].
Tumors — Persons with NF1 develop both benign and malignant tumors at increased frequency throughout life [22,23]. Neurofibromas are the most common type of benign tumor that develops in persons with NF1. OPGs and other gliomas are the predominant type of intracranial neoplasms, and malignant peripheral nerve sheath tumors (MPNSTs) are the most common non-central nervous system (CNS) malignancy [23-25]. The overall risk of malignancy in NF1 is higher compared with the general population, mostly driven by the higher risk of MPNST. Moreover, individuals with NF1 are diagnosed with cancer at a younger age compared with the general population [23,26-29].
Peripheral neurofibromas — Neurofibromas are benign peripheral nerve sheath tumors that are composed of a mixture of Schwann cells, fibroblasts, perineurial cells, and mast cells [30]. It is in the Schwann cells where loss of both NF1 alleles occurs, indicating that this is the primary tumor cell of the neurofibroma [10,31]. (See 'Soft tissue sarcomas' below.)
Neurofibromas may appear as focal growths or extend longitudinally along a nerve and involve multiple fascicles. The latter are referred to as plexiform neurofibromas. Neurofibromas may be located in the skin (cutaneous neurofibromas), along peripheral nerves under the skin or deeper inside the body, and along nerve roots adjacent to the spine.
The number and size of all types of neurofibromas may increase during pregnancy, suggesting that these tumors have a hormone-responsive component. In a report of 247 pregnancies in 105 individuals, growth of new lesions and enlargement of existing lesions were reported in 60 and 55 percent of cases, respectively [32].
In adulthood, the growth pattern of neurofibromas tends to slow, and many tumors shrink over time. In a prospective cohort study that included 47 adults with NF1 (median age 42 years at baseline) who were followed with serial whole-body MRI for a median of 10.4 years, 63 percent of internal tumors shrank volumetrically by ≥20 percent without treatment, and only 17 percent enlarged by ≥20 percent [33]. Growth patterns were heterogeneous among tumors within the same patient, and there were no strong predictors of growth identified.
Cutaneous neurofibromas — Discrete cutaneous neurofibromas are the most common type. They consist of soft, fleshy, sessile or pedunculated tumors [34]. They move with the skin on examination and are not tender. Some are located within the dermis and can be palpated as a soft spot in the skin, often with an overlying violaceous discoloration. These cutaneous lesions usually begin to appear just before or during adolescence, although small lesions can be seen in younger children, especially if the skin is viewed with side lighting. They tend to increase in size and number with age and vary in number from just a few to thousands, with the highest density occurring over the trunk (picture 5).
Cutaneous neurofibromas are benign and do not carry a risk of malignant transformation, but they often represent a major cosmetic problem in adults. Pruritus associated with accelerated growth of neurofibromas may be a prominent and distressing symptom.
Plexiform neurofibromas — Plexiform neurofibromas may be located superficially and associated with overgrowth of skin and soft tissues (picture 6 and image 1), may be located deep inside the body, or may have both superficial and deep components. Cutaneous involvement tends to be diffuse, with no discernible nerve fibers, although small plaques of cutaneous plexiform tumors may have palpable cords of thickened nerves. Deeper plexiform neurofibromas tend to appear as thickened nerves and can grow into a complex mass consisting of a network of enlarged nerves. The lesions are usually congenital and tend to grow most rapidly during childhood [35,36]. Whole-body imaging reveals plexiform neurofibromas in approximately 50 percent of patients with NF1 [34].
Plexiform neurofibromas represent a major cause of morbidity and disfigurement in individuals with NF1, and symptomatic plexiform neurofibromas are associated with increased mortality [37]. Plexiform neurofibromas may compress the airway or spinal cord and can transform into MPNSTs. Orbital plexiform neurofibromas are associated with sphenoid wing dysplasia, which can lead to enophthalmos or, if there is substantial orbital tumor, exophthalmos. The sphenoid wing dysplasia can be progressive [38,39]. The most common feature of malignant transformation of an existing plexiform neurofibroma is a painful, expanding lesion. (See 'Malignant peripheral nerve sheath tumors' below.)
Nodular neurofibromas — Nodular neurofibromas are discrete lesions that may grow under the skin, where they appear as firm, rubbery masses that may be tender, or occur deeper inside the body (image 2 and image 3). Some can enlarge to the point where they compress surrounding structures or cause pain, but they do not tend to invade surrounding tissues like plexiform neurofibromas. They may take up 18-fluorodeoxyglucose, as occurs in MPNST [40], and may have pathologic features including nuclear atypia, some mitotic activity, and dense cellularity, referred to as "atypical neurofibroma" or "atypical neurofibromatous neoplasms of uncertain biologic potential" (ANNUBP) [41]. Atypical neurofibromas have homozygous deletion of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) in addition to loss of both NF1 alleles [42-44] and may be premalignant lesions.
Optic pathway gliomas — OPGs occur in approximately 15 percent of children younger than six years of age with NF1 [45]. They rarely occur as new tumors in older children and adults [46,47]. OPGs are typically low-grade pilocytic astrocytomas [46,47]. They can arise anywhere along the anterior visual pathway to the optic radiations and involve the optic nerves, chiasm, and postchiasmal optic tracts (image 4). A retrospective magnetic resonance imaging (MRI) study of 562 adults and children with NF1 revealed an overall prevalence of optic pathway tumors of 9.3 percent [48]. (This may have been lower than in other studies due to the wide age range of persons included in the study.) Of 52 persons with optic glioma, 29 had intraorbital tumors, 32 had prechiasmatic tumors, 17 had involvement of the optic chiasm, and 19 had extension to the optic radiations; 29 had involvement of two or more regions. Visual decline was found in 17 of 52 persons, 7 of whom required treatment.
Many children with NF1 and OPGs have normal vision. A minority of children become symptomatic with progressive vision loss. Risk factors for visual loss include age less than two years, female sex, and tumor involvement of the postchiasmal optic pathway [49-52]. Symptoms and signs of OPG may include decreased visual acuity or color vision, abnormal pupillary function, proptosis, and optic nerve atrophy [53-55]. Optical coherence tomography to assess retinal nerve fiber thickness can provide a means of following visual function over time in those with optic glioma [56]. (See "Optic pathway glioma" and "Neurofibromatosis type 1 (NF1): Management and prognosis", section on 'Optic pathway gliomas and other low-grade gliomas'.)
Premature or delayed puberty due to OPGs — Children with tumors involving the optic chiasm occasionally present with either premature or delayed puberty caused by hypothalamic involvement [24]. Detecting precocious puberty early in patients with NF1 is important because it may indicate the presence of a clinically significant OPG, although abnormal puberty can occur in the absence of OPG. In addition, treatment can minimize the complications of accelerated linear bone growth and premature development of secondary sexual characteristics. One of the earliest signs of precocious puberty is accelerated linear growth, which highlights the importance of maintaining accurate growth charts using standards for children with NF1 [57,58]. (See "Definition, etiology, and evaluation of precocious puberty" and 'Growth' below.)
Other central nervous system neoplasms — In addition to OPGs, individuals with NF1 are at an increased risk for developing other CNS neoplasms, particularly low-grade astrocytomas, brainstem gliomas, and high-grade gliomas [23,24,46,59-62]. The most frequent clinical presentation is that of increased intracranial pressure, although lesions are often asymptomatic and are noted as incidental findings if brain imaging is performed. Patients with symptoms are more likely to progress and require treatment [62].
Brainstem gliomas in children with NF1 may be asymptomatic and not require therapy [63]. Patients who present with symptomatic brainstem gliomas are more likely to have higher-grade tumors (World Health Organization [WHO] grade 3 or 4) requiring treatment [61]. In adults with suspected gliomas (brainstem or otherwise), a biopsy is advised whenever feasible to confirm an integrated molecular diagnosis and to guide therapy [64-66]. The clinical behavior of gliomas in adults with NF1 is often aggressive, even for patients with low-grade tumors [67].
Soft tissue sarcomas — Patients with NF1 are at an increased risk of developing soft tissue sarcomas, such as MPNSTs and rhabdomyosarcoma (RMS), and gastrointestinal stromal tumors (GISTs) [23].
Malignant peripheral nerve sheath tumors — MPNSTs, previously called neurofibrosarcomas, usually arise within preexisting plexiform or nodular neurofibromas (image 5). The primary care provider should be alert to the possibility of this highly malignant tumor, particularly in teenagers and young adults. The first presentation of malignant transformation often is development of significant and constant pain, change in consistency from soft to hard, or rapid growth of a nodule within an existing plexiform neurofibroma [68,69]. MRI findings suggestive of malignant change include large size, depth below the fascial layer, and necrosis [70]. Positron emission tomography (PET) imaging with 18-fluorodeoxyglucose may be helpful in distinguishing MPNST from benign plexiform or nodular neurofibromas [71-73].
The lifetime risk of developing an MPNST in patients with NF1 ranges from 8 to 13 percent, with a higher risk at older ages. The risk of NF1-associated MPNST by age 30, 50, and 85 years is 8.5, 12.3, and 15.8 percent, respectively [74,75]. Among children with MPNSTs, 20 to 50 percent have NF1 [68]. Those with NF1 tend to have larger tumors at diagnosis [76].
MPNSTs are discussed in greater detail separately. (See "Peripheral nerve tumors", section on 'Malignant peripheral nerve sheath tumors' and "Neurofibromatosis type 1 (NF1): Management and prognosis", section on 'Malignant peripheral nerve sheath tumors'.)
Rhabdomyosarcoma — RMS is encountered more frequently in persons with NF1 than in the general population [77]. RMS in association with NF1 tends to present at an early age, often arises in a genitourinary site, and is usually of the embryonal histologic subtype [23,77]. (See "Rhabdomyosarcoma in childhood and adolescence: Epidemiology, pathology, and molecular pathogenesis".)
Gastrointestinal stromal tumors — Persons with NF1 are also at an increased risk of developing GISTs, which are soft tissue tumors that arise within the stromal compartment of the gastrointestinal tract [78-81]. In the setting of NF1, GISTs frequently occur in the small intestine (more than 70 percent), are often multiple, and have a different molecular pathology from sporadic GISTs in persons who do not have NF1. (See "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors".)
Glomus tumors — Glomus tumors arise in the tips of the fingers and toes under the nail bed (image 6) and present with pain, tenderness, and sensitivity to cold. They are associated with NF1 [82] and are important to recognize because the pain is readily relieved by surgical removal of the tumor.
Other tumors — NF1 patients have an increased risk of certain other malignancies, such as juvenile myelomonocytic leukemia and pheochromocytoma, although genetic etiologies other than NF1 are more common causes of these malignancies. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia", section on 'Juvenile myelomonocytic leukemia' and "Pheochromocytoma in genetic disorders".)
Females with NF1, particularly those under 50 years of age, are at increased risk of breast cancer [83]. Breast cancers tend to be estrogen receptor negative and human epidermal growth factor receptor 2 (HER2) positive and are associated with a younger age at diagnosis and less favorable prognosis than non-NF1-associated breast cancers [23,84].
Whether other common malignancies occur at higher rates in patients with NF1 is uncertain [28]. In one large cohort study, patients with NF1 had increased odds of several other cancers compared with the general population, including neuroendocrine tumors, melanoma, ovarian cancer, and Hodgkin lymphoma [23].
Bone abnormalities — Bone abnormalities in NF1 include pseudoarthrosis and bone dysplasia, which are part of the United States National Institutes of Health (NIH) Consensus Conference criteria for the disease, as well as short stature, scoliosis, nonossifying fibromas, sphenoid dysplasia, and osteoporosis [85,86]. (See 'Diagnostic criteria' below and 'Plexiform neurofibromas' above.)
Long bone dysplasia and pseudoarthrosis — Long bone dysplasia presents in infants or young children as anterolateral bowing of the tibia, which progresses to narrowing of the medullary canal, cortical thickening, and fracture [87,88]. The diagnosis may be overlooked until pathologic fractures occur with weight bearing or when walking is first attempted in toddlers. Approximately one-half of fractures occur before the patient is two years of age.
A pseudoarthrosis is a false joint that forms when there is nonunion of bone fragments at the site of a long bone fracture. It severely compromises function in the affected limb. Pseudoarthrosis in NF1 occurs in infancy in approximately 5 percent of persons with NF1 and results from impaired healing due to bone dysplasia [87]. It has a male predominance (1.7:1). NF1 is the most common cause of long bone pseudoarthrosis, accounting for 50 to 80 percent of cases; therefore, evaluation for NF1 should be performed in a child with this condition.
Other bone lesions — Other skeletal lesions include vertebral defects, such as scalloping caused by dural ectasia, nonossifying fibromas within long bones, and sphenoid wing dysplasia, which may present as facial asymmetry. Rarely, a bone defect can occur in the lambdoidal suture, which is easily palpable [89,90].
Growth — Children with NF1 frequently have short stature. In a database of 569 White North American patients with NF1, 13 percent had a height ≥2 standard deviations below the population mean [57]. Decreased height velocity during puberty is seen in adolescents with NF1 and is more prominent in males than females [91]. Growth curves for children with NF1 are available and can aid the clinician in determining if the degree of short stature is consistent with the diagnosis of NF1 or is more severe [57,58]; the latter suggests an additional cause and requires evaluation. A study of birth weight in infants with NF1 showed an increase in both birth weight and head circumference in association with NF1, although NF1 in the mother was associated with a decrease in birth weight [92]. (See "Diagnostic approach to children and adolescents with short stature" and "Causes of short stature".)
Scoliosis — Scoliosis occurs in 10 to 25 percent of persons with NF1 [87,93,94]. This condition frequently becomes apparent at 6 to 10 years of age or in early adolescence. Scoliosis in children with NF1 most commonly affects the thoracic spine and tends to be sharply angulated and dystrophic. Sometimes there is an associated paraspinal plexiform neurofibroma. (See "Adolescent idiopathic scoliosis: Clinical features, evaluation, and diagnosis".)
Osteoporosis — Persons with NF1 have lower bone density per age compared with general population controls [85,95]. The severity of decreased bone density can range from osteopenia to osteoporosis. The etiology of this decrease in bone density is unknown and appears to be largely independent of vitamin D-related dysregulation [95]. A survey from Finland revealed an increased risk of fractures in both children and adults over the age of 40 years with NF1 (threefold and fivefold increased relative risk, respectively) compared with population controls of similar age and sex distribution [96].
Neurologic abnormalities — Neurologic disorders include cognitive deficits, learning disabilities, headaches, and seizures. Gross and fine motor developmental delays are also seen. Macrocephaly is a common feature. Dural ectasia along the spine can result in symptoms such as pain resulting from nerve root compression [97].
Cognitive deficits and learning disabilities — Cognitive deficits, learning disabilities, and autism spectrum disorders occur with higher frequency in children with NF1 [98,99]. A study of 81 children with NF1 found moderate to severe impairment involving one or more domains of cognitive function in 66 (81 percent) [100]. Intelligence quotient (IQ) scores are 5 to 10 points lower in children with NF1 compared with the general population or unaffected sibling controls [101]. The incidence of intellectual disability (full scale IQ <70) in this disorder is 4 to 8 percent, only slightly higher than that of the general population (2 to 3 percent). Thus, a child with NF1 and intellectual disability should be evaluated for other causes of cognitive impairment (eg, fragile X syndrome). Autism spectrum disorder also occurs with increased frequency in association with NF1, although here, too, alternative causes should be explored [102,103]. (See "Fragile X syndrome: Clinical features and diagnosis in children and adolescents".)
One-half of the children in one series performed poorly on tasks of reading, spelling, and mathematics, but only 20 percent had specific learning disabilities (defined by discrepancy between ability [IQ] and academic achievement) [100]. Specific learning disabilities occur in up to 65 percent of patients with NF1 in other series [101]. Affected children demonstrate a range of neuropsychologic impairments, including poor performance on nonverbal learning problems (ie, difficulty with written work, poor attention, and decreased organizational skills), tests of visuospatial function, language-based learning tasks (ie, reading and spelling) [101], and impaired social skills [104]. Attention deficit hyperactivity disorder (ADHD) occurs in 30 to 40 percent of children with NF1 [100,105]. Executive function impairment in the areas of planning and problem solving that are not directly related to inattention level are seen [106,107]. (See "Neurofibromatosis type 1 (NF1): Management and prognosis", section on 'Cognitive and learning deficits' and "Specific learning disorders in children: Clinical features" and "Specific learning disorders in children: Evaluation" and "Attention deficit hyperactivity disorder in children and adolescents: Clinical features and diagnosis".)
Problems with speech articulation are also common, and voice may be hypernasal. Auditory processing deficits and impaired speech discrimination can also be seen [108].
Seizures — Seizures are approximately twice as common in patients with NF1 compared with the general population, with a prevalence of approximately 4 to 6 percent [109-111]. Seizures can be of any type and begin at any age and usually are not attributable to a mass lesion in the brain [112], though focal seizures may be due to an intracranial neoplasm. Thus, new seizures should prompt repeat neuroimaging, even if previous imaging was normal. (See "Seizures and epilepsy in children: Classification, etiology, and clinical features".)
Macrocephaly — Head size is generally larger in persons with NF1 [112]. This may present as relative macrocephaly compared with height or absolute macrocephaly [113]. It is caused by increased brain volume. Rarely, hydrocephalus may occur due to aqueductal stenosis [59,114]. Chiari malformation is seen in some children with NF1 [115]. (See 'Increased brain volume (megalencephaly)' below.)
Peripheral neuropathy — Peripheral neuropathy is much less common in NF1 than in neurofibromatosis type 2 (NF2), with reports of nerve compression in up to 4 percent of patients and spinal root compression in up to 3 percent of patients with NF1 [18]. By comparison, clinical symptoms of peripheral neuropathy occur in almost 50 percent of patients with NF2 [116]. Nevertheless, peripheral neuropathy can be a severe complication of NF1 that is associated with morbidity and may be a marker of a more severe phenotype with regard to spinal complications and risk of MPNST [117]. Polyneuropathy can also occur in the absence of a compressive lesion [118,119] and may take the form of small fiber neuropathy [120]. (See "NF2-related schwannomatosis (formerly neurofibromatosis type 2)" and 'Malignant peripheral nerve sheath tumors' above.)
Congenital heart disease — The incidence of congenital heart disease (CHD) is increased in NF1. In one study of 493 genotyped patients with NF1, 62 (12.6 percent) had some form of CHD [121]. The most common was pulmonic stenosis (21 persons), followed by mitral valve anomalies (20 persons) and septal defects (10 persons). A variety of other CHDs, including tetralogy of Fallot and thickening of the ventricular wall, were seen less often. Those with CHD were more likely to show Noonan syndrome-like facial features and have either whole gene deletions or nontruncating NF1 gene mutations.
Hypertension — Hypertension is a frequent finding in adults with NF1 and may develop during childhood. Hypertension is considered primary (essential) in most cases, but vascular lesions producing renovascular hypertension are more frequent in patients with NF1. Thus, evaluation for renal artery stenosis should be initiated in children with NF1 and hypertension [122].
Renovascular lesions can be detected in patients who are still normotensive. The frequency with which such patients will develop hypertension is not known. Renal tubular and glomerular dysfunction may also occur with increased frequency compared with healthy controls [123].
A much less common cause of hypertension in NF1 is pheochromocytoma, although consideration of this possibility in a hypertensive person with NF1 is important given the potential morbidity [124,125]. (See "Definition and diagnosis of hypertension in children and adolescents" and "Overview of hypertension in adults" and "Pheochromocytoma and paraganglioma in children" and 'Other tumors' above and "Neurofibromatosis type 1 (NF1): Management and prognosis", section on 'Hypertension' and "Neurofibromatosis type 1 (NF1): Management and prognosis", section on 'Severe hypertension'.)
Other manifestations — An increased risk of constipation and irritable bowel syndrome has been reported in association with NF1 [126]. Very rarely, persons with NF1 may develop cardiovascular complaints or airway compromise due to mediastinal neurofibromas or MPNST metastases to the heart and lung [127-129]. Pulmonary hypertension [130-132], pulmonary artery stenosis [133], interstitial lung disease [134,135], and bullous lung disease [136] have also been reported. These findings are more common in adults, but radiographic signs may be seen in children [137]. Other vascular lesions may cause stenosis of major vessels, including the internal carotid, resulting in moyamoya disease [138-140]. In rare instances, arterial dissection can occur, sometimes leading to life-threatening hemorrhage [141]. (See 'Plexiform neurofibromas' above and 'Malignant peripheral nerve sheath tumors' above and 'Other tumors' above and "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis".)
Quality of life — Given the diverse manifestations, neurocognitive problems, and risk of disfigurement and even death, it is not surprising that persons with NF1 report a decreased quality of life [142]. Affected adults and children may experience problems with self-image, anxiety, and chronic pain [142-149].
Segmental NF1 — Segmental NF1 is due to mosaicism for an NF1 gene mutation. The presentation of segmental and generalized NF1 is similar with regard to the age of appearance of the specific features, with a few exceptions [3,150]. In segmental NF1, pigmentary features and plexiform neurofibromas tend to present in children, while cutaneous neurofibromas develop in adults. Lisch nodules may be present in one or both eyes. In most persons, the affected area is limited to one side, with involvement ranging from a narrow strip to one-half of the body. More serious complications of NF1, such as OPGs, pseudoarthrosis, plexiform neurofibromas, and learning difficulties, are uncommon in those with segmental NF1, occurring in 5.6 percent in one series of 124 patients [3].
NEUROIMAGING FINDINGS — Brain neuroimaging abnormalities are frequently detected in persons with NF1 [151]. These include NF-associated bright spots and increased brain volume.
NF-associated bright spots — Focal areas of increased signal intensity were first identified on T2-weighted MRI of the brain in children with NF1 [152,153]. The term "unidentified bright objects" (UBOs) is discouraged because it can be upsetting to parents/caregivers. Bright spots are seen commonly in children with NF1 but may disappear in adulthood. They occur most often in the basal ganglia, cerebellum, brainstem, and subcortical white matter and are thought to represent increased fluid within the myelin associated with dysplastic glial proliferation [152]. They are not part of the consensus diagnostic criteria [154]. They do not behave in a malignant or premalignant manner and are not associated with focal neurologic deficits, although one retrospective study of 68 children noted that 28 percent developed a brain tumor, most often in the basal ganglia or cerebellum, that required treatment [155].
Data are conflicting on the relationship between NF-associated bright spots and cognitive function. In one report, 25 of 40 children (62 percent) with NF1 had bright spots present on MRI [156]. These children had significantly lower intelligence quotient (IQ) and language scores and impaired visuomotor integration and coordination compared with children without them. In another study, the number of locations containing spots accounted for much of the lowering of IQ scores in NF1-affected persons compared with unaffected siblings [157]; however, in a third series, these lesions were not associated with intellectual impairment [158]. (See 'Cognitive deficits and learning disabilities' above.)
Increased brain volume (megalencephaly) — Brain volumes are increased in patients with NF1 [113,151,159,160]. (See 'Macrocephaly' above and 'Cognitive deficits and learning disabilities' above.)
Cerebrovascular dysplasia — Several retrospective series have noted abnormal cerebral vasculature (eg, moyamoya disease, intracranial aneurysm) in 2 to 6 percent of children with NF1 who underwent neuroimaging [138,161,162]. Most were asymptomatic despite angiographic progression, but some required surgery for revascularization.
DIAGNOSIS — The diagnosis of NF1 is based upon the presence of characteristic clinical features (table 2). Genetic testing is often not required to make the diagnosis but can be helpful in confirming the diagnosis for children who do not meet diagnostic criteria without genetic data or only demonstrate café-au-lait macules and axillary freckling.
Children suspected of having NF1 should be evaluated by a multidisciplinary team that includes pediatric neurologists, geneticists, and ophthalmologists (table 3). This team should examine the child for diagnostic criteria and treatable complications, provide anticipatory guidance, and refer to specialists as needed. Consensus guidelines for management of children [163] and adults [75] with NF1 have been published.
The initial screening evaluation should confirm the diagnosis by identifying clinical features of NF1. History should be obtained regarding symptoms associated with the disorder, such as pain, visual complaints, weakness or neurologic deficits, headaches, and seizures. The developmental history and school progress should be reviewed. Physical examination should focus on skin, skeletal, and neurologic systems. Ophthalmologic evaluation should be performed to identify Lisch nodules and early signs of optic pathway glioma (OPG). (See 'Clinical manifestations' above and 'Diagnostic criteria' below.)
Diagnostic criteria — The diagnostic criteria developed by the United States National Institutes of Health (NIH) Consensus Conference in 1987 [164] and updated in 1997 [165] and 2021 [154] are based upon specific clinical features of NF1 (table 2). In an individual who does not have a parent with NF1, the diagnosis is established if at least two of the following criteria are met:
●Six or more café-au-lait macules >5 mm in diameter in prepubertal and >15 mm in diameter in postpubertal individuals. For each lesion, the longest diameter is measured. Ordinary room light (not a Wood's lamp) is used.
●Two or more neurofibromas of any type or one plexiform neurofibroma (picture 7).
●Freckling in the axillary or inguinal region.
●Optic pathway glioma (OPG).
●Two or more Lisch nodules (iris hamartomas) or two or more choroidal abnormalities.
●A distinctive bony lesion, such as sphenoid dysplasia, anterolateral bowing of the tibia, or long bone pseudoarthrosis.
●A heterozygous pathogenic NF1 variant with variant allele fraction of 50 percent in apparently normal tissue (eg, white cells).
A child of a parent with NF1 can be diagnosed if one or more of these criteria are met.
The diagnostic criteria are both highly specific and sensitive in all but the youngest children [14], with 97 percent of affected persons meeting the original NIH diagnostic criteria by eight years of age and the remainder meeting criteria by 20 years of age. In a study of 1893 persons with NF1 younger than 21 years of age, approximately 46 percent of sporadic NF1-affected persons failed to meet the NIH criteria by one year of age [14]. Thus, young children who have only one clinical manifestation and no family history of NF1 should continue to be monitored for appearance of other manifestations since a definitive diagnosis usually can be made by the time the child is four years of age. Genetic testing can be considered to make a molecular diagnosis.
Genetic testing — Genetic testing can be performed to confirm the diagnosis in questionable cases and to help direct screening of family members (ie, perform targeted testing for the mutation identified in the proband rather than a comprehensive mutation analysis of the entire gene). Genetic testing is required for prenatal or preimplantation diagnosis. A positive NF1 mutation test does not predict the severity or complications of the disorder, with some specific exceptions. (See 'Pathogenesis' above.)
Pathogenic variants associated with the clinical diagnosis of NF1 disrupt the function of the NF1 gene. Because of the large size of the gene and the heterogeneity of mutations, molecular testing includes sequencing of the entire coding region as well as tests for deletions or rearrangements of a portion or the entire gene and examination for intronic variants that disrupt splicing. Molecular testing is clinically available and is reported to find the causative pathogenic variant in approximately 95 percent of patients who carry the clinical diagnosis of NF1 [166]. Thus, a negative test does not completely exclude the diagnosis. A negative test may also represent mosaicism for a pathogenic variant (for example, in segmental NF1 where blood may be negative) or the possibility of a different disorder. (See 'Differential diagnosis' below.)
Several thousand distinct pathogenic NF1 variants have been identified in affected persons [7]. Few obvious genotype-phenotype correlations have been demonstrated in patients with small mutations (<20 base pairs) of the NF1 gene. The c.2970-2972 delAAT (p.M992del) mutation is associated with a very mild phenotype in the majority of cases [167]. A severe phenotype including plexiform neurofibromas, spinal neurofibromas, optic glioma, skeletal dysplasia, and predisposition to malignancy is associated with missense variants in codons 844 to 848 [168]. Persons with p.Met1149, p.Arg1276, or p.Lys1423 missense variants tend to have a Noonan syndrome-like phenotype [169]. The last two pathogenic variants are associated with an increased risk of congenital heart defects. p.Arg1276 is also associated with a high burden of spinal neurofibromas and p.Met1149 with café-au-lait macules but not tumors.
Approximately 1 to 5 percent of persons with NF1 have large deletions that encompass 1.4 to 1.5 Mb of deoxyribonucleic acid (DNA) and include the entire NF1 gene [170]. Such persons have a higher incidence of intellectual disability, developmental delay, dysmorphic facial features, and connective tissue abnormalities, as well as an earlier appearance of cutaneous neurofibromas. They also appear to have an increased risk of malignant peripheral nerve sheath tumors (MPNSTs) [171,172], which is in part due to deletion of the SUZ12 polycomb repressive complex 2 subunit (SUZ12) gene that is contiguous to NF1 [173,174].
Persons with other conditions, including Legius syndrome [170,175-177] and constitutional mismatch repair-deficiency (CMMR-D) syndrome [178-180], may manifest both café-au-lait macules and axillary freckling, and those with Noonan syndrome may present with café-au-lait macules [181,182]. Thus, there is increasing use of genetic testing in the diagnosis of NF1 for patients who meet only these two NIH criteria in addition to those with only one criterion. A positive genetic test may shorten the period of diagnostic uncertainty. In addition, appropriate screening evaluations (eg, ophthalmic screens) are initiated promptly if the test is positive for an NF1 mutation. If the NF1 mutation testing is negative, then the diagnostic laboratory may perform sprouty-related EVH1 domain-containing 1 (SPRED1) mutation testing to evaluate for Legius syndrome. If both are negative, then genetic testing of the four mismatch repair genes or Noonan syndrome should be considered. The parents and caregivers of young children with multiple café-au-lait macules alone should understand the risks and benefits of genetic analysis before proceeding with testing. (See 'Differential diagnosis' below.)
Screening family members — A detailed family history should be obtained to detect possible symptoms of NF1 when the diagnosis is made in a child. When possible, biologic parents and siblings should be examined for the characteristic signs (table 2). This evaluation includes a complete examination of the skin and a slit lamp examination of the eyes because of the variable expressivity of this disorder. (See 'Pathogenesis' above.)
Genetic screening of family members is discussed above. (See 'Genetic testing' above.)
Prenatal testing — Amniocentesis or chorionic villus sampling can be performed to obtain a sample for genotyping the fetus if the precise mutation of an affected family member with NF1 is known. Preimplantation genetic testing (PGT) to identify those embryos that do not carry a known familial NF1 mutation is also possible [136]. (See "Neurofibromatosis type 1 (NF1): Management and prognosis", section on 'Genetic counseling'.)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of NF1 includes Legius syndrome, constitutional mismatch repair-deficiency (CMMR-D) syndrome, NF2-related schwannomatosis (NF2), and Noonan syndrome. Genetic testing can distinguish NF1 from these other syndromes. The table (table 3) provides a differential diagnosis of café-au-lait macules.
Legius syndrome — The clinical features of Legius syndrome include a subset of those of NF1 (multiple café-au-lait macules, axillary freckling, and macrocephaly) but lack neurofibromas and central nervous system (CNS) tumors [154,176]. Legius syndrome is an autosomal dominant NF1-like disorder that results from germline loss-of-function variants in SPRED1 (table 4) [175,177]. SPRED1 is a member of the SPROUTY/SPRED family of proteins that act as negative regulators of Ras-Raf kinase interaction and mitogen-activated protein kinase (MAPK) signaling. Melanocytes from a café-au-lait spot demonstrated both the germline SPRED1 mutation and an acquired somatic mutation in the wildtype SPRED1 allele, suggesting that complete SPRED1 inactivation is needed to generate a café-au-lait spot in this syndrome [175].
Constitutional mismatch repair-deficiency syndrome — CMMR-D syndrome is a rare, autosomal recessive disorder caused by inheritance of deleterious mutations in both copies of one of the four mismatch repair genes [178-180]. The main clinical manifestation that CMMR-D shares with NF1 is café-au-lait macules. Axillary freckling and Lisch nodules have also been reported in CMMR-D. The primary clinical difference between the two disorders is the types of malignancies seen with each. In CMMR-D, hematologic malignancies typically develop in infancy to early childhood, brain tumors (primarily glioblastoma) in midchildhood, and colorectal cancer in adolescence to young adulthood. A variety of other tumors (eg, rhabdomyosarcoma [RMS] and optic pathway glioma [OPG]) are less commonly seen in CMMR-D. Heterozygous mutations in one of the MMR genes cause Lynch syndrome (hereditary nonpolyposis colorectal cancer). (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis".)
Consensus guidelines for testing of CMMR-D have been published [179]. Testing is recommended in those who present with one diagnostic feature of NF1 not sufficient to make a diagnosis (this would usually be café-au-lait spots); test negative for NF1 and SPRED1; and have either a family history of consanguinity, Lynch syndrome in a parent, a sibling who has had a childhood malignancy, or, in the patient, "atypical" café-au-lait spots (irregularly marginated spots, for example), one or more pilomatricomas, agenesis of the corpus callous, nontherapy-induced cavernoma, or multiple developmental vascular anomalies.
NF2-related schwannomatosis — NF2 and NF1 are caused by pathogenic variants in genes on different chromosomes that encode proteins of distinct function. Nonetheless, partial overlap in the clinical manifestations of these inherited disorders can occasionally lead to confusion. (See "NF2-related schwannomatosis (formerly neurofibromatosis type 2)".)
Key differences between NF1 and NF2 include:
●Café-au-lait macules can be seen but are much less frequent in NF2, and Lisch nodules are not seen.
●The schwannomas associated with NF2 do not undergo malignant transformation into a malignant peripheral nerve sheath tumor (MPNST).
●The spinal root tumors that are seen with both NF2 and NF1 are schwannomas in NF2 and neurofibromas in NF1.
●NF2 is not associated with the cognitive impairment that is often seen with NF1.
●NF2 is associated with a very high prevalence of bilateral vestibular schwannomas and meningiomas.
Noonan syndrome — Noonan syndrome is characterized principally by short stature, webbed neck, characteristic facial features (hypertelorism, downward eye slant, and low-set ears), and pulmonic stenosis [181,182]. Affected individuals may have café-au-lait spots, sometimes more than six that are larger than 5 mm, which fulfills a diagnostic criterion for NF1 in children. In addition, the facial features of Noonan syndrome are sometimes also seen in individuals with NF1. Noonan syndrome is due to mutation in one of several genes in the Ras signaling pathway, especially protein tyrosine phosphatase nonreceptor-type 11 (PTPN11). (See "Noonan syndrome" and "Pulmonic stenosis in infants and children: Clinical manifestations and diagnosis".)
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)")
Information for patients about NF1 is available online through the Children's Tumor Foundation.
SUMMARY AND RECOMMENDATIONS
●What is NF1? – Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder with manifestations that include pigmentary changes, benign tumors of peripheral nerve sheaths called neurofibromas, increased risk of central nervous system (CNS) gliomas and other malignant tumors, and learning disabilities. The most visible features are the multiple café-au-lait macules and the associated cutaneous neurofibromas (picture 5). (See 'Introduction' above.)
●Pathogenesis – NF1 is an autosomal dominant disorder caused by pathogenic variants in the NF1 gene that encodes the protein neurofibromin. Penetrance is complete, but expression is highly variable. Segmental NF1 is caused by somatic mosaicism due to a postzygotic mutation in the NF1 gene. (See 'Pathogenesis' above.)
●Clinical manifestations – The clinical manifestations of NF1 emerge over time (table 1). Approximately half of individuals with sporadic NF1 meet clinical criteria for diagnosis in the first year of life, and nearly all do so by eight years of age. (See 'Clinical manifestations' above.)
•Café-au-lait macules – Café-au-lait macules are flat, uniformly hyperpigmented macules that appear during the first year after birth and usually increase in number during early childhood (picture 1). The presence of six or more café-au-lait macules is highly suggestive, but not diagnostic, of NF1. (See 'Café-au-lait macules' above.)
•Axillary and inguinal freckling – Freckles are smaller in size than café-au-lait macules, appear later, and usually occur in clusters in skin folds rather than randomly (picture 2 and picture 3). (See 'Freckling' above.)
•Lisch nodules – Lisch nodules are raised, tan-colored hamartomas of the iris. Large nodules on a light-colored iris can be seen with a direct ophthalmoscope, but slit lamp examination is more reliable. Lisch nodules are specific to NF1 but are uncommon before the age of six years. (See 'Lisch nodules' above.)
•Neurofibromas – Discrete cutaneous neurofibromas are the most common type of neurofibroma in NF1 (picture 5); other forms include plexiform and nodular. Cutaneous neurofibromas usually appear just before or during adolescence, although small lesions can be seen in younger children. (See 'Peripheral neurofibromas' above.)
•Other tumors – People with NF1 develop both benign and malignant tumors at increased frequency throughout life. Optic pathway gliomas (OPGs) occur in approximately 15 percent of children by six years of age. Less common tumors include sarcomas, glomus tumors, hematologic malignancies, and breast cancer. (See 'Tumors' above.)
•Bone abnormalities – Bone abnormalities in NF1 include bone dysplasia, pseudoarthrosis, short stature, scoliosis, nonossifying fibromas, sphenoid dysplasia, and osteoporosis. (See 'Bone abnormalities' above.)
•Neurologic abnormalities – Neurologic disorders include cognitive deficits, learning disabilities, headaches, seizures, developmental delays, and macrocephaly. (See 'Neurologic abnormalities' above.)
•Others – Hypertension is a frequent finding in adults with NF1 and may develop during childhood. (See 'Hypertension' above.)
●Diagnosis – The diagnosis of NF1 is based upon the presence of characteristic clinical features (table 2). Genetic testing is not required to make the diagnosis but can be helpful in confirming the diagnosis for children who do not meet diagnostic criteria or only demonstrate café-au-lait macules and axillary freckling.
Children suspected of having NF1 should be evaluated by a multidisciplinary team that includes pediatric neurologists, geneticists, and ophthalmologists. (See 'Diagnosis' above.)
●Differential diagnosis – The differential diagnosis of NF1 includes Legius syndrome (table 4), constitutional mismatch repair-deficiency (CMMR-D) syndrome, NF2, and Noonan syndrome. (See 'Differential diagnosis' 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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