Neurofibromatosis 1

Cutaneous Features

Café au lait spots and freckling. Multiple café au lait spots occur in nearly all affected individuals, and intertriginous freckling develops in almost 90%.

Typically, the characteristic café au lait spots in individuals with NF1 are ovoid in shape with well-defined borders, uniform in color (a little darker than the background pigmentation of the individual's skin), and about 1-3 cm in size; however, they may be smaller or much larger, lighter or darker, or irregular in shape. The pigmentation may also be irregular, with freckling or a more deeply pigmented smaller café au lait spot within a larger more typically colored lesion. Café au lait spots are flat and flush with the surrounding skin; if the skin of the lesion is raised or has an unsually soft or irregular texture in comparison to the surrounding skin, an underlying plexiform neurofibroma is likely. The darker pigmentation of café au lait spots may be difficult to see in people with very fair skin or very dark skin, where the color of the lesions is similar to that of the rest of the skin. A Wood's light is useful in such cases to demonstrate the pigmented macules. Café au lait spots are not seen on the palms or soles in people with NF1 but can occur almost anywhere else on the body.

Clusters of freckles are frequent in sun-exposed areas and may also be seen diffusely over the trunk, proximal extremities, and neck in people with NF1. Similar freckling is common in fair-skinned people who do not have NF1. However, people with NF1 also develop freckles in areas where skin rubs against skin – in the axilla, groin, and under the breasts in women. These freckles look like any others: it is only their location that is unusual.

Neurofibromas. Numerous benign cutaneous neurofibromas are usually present in adults with NF1.

Discrete cutaneous and subcutaneous neurofibromas are rare before late childhood. The total number of neurofibromas seen in adults with NF1 varies from a few to hundreds or even thousands. Additional cutaneous and subcutaneous neurofibromas continue to develop throughout life, although the rate of appearance may vary greatly from year to year. Many women experience a rapid increase in the number and size of neurofibromas during pregnancy [Roth et al 2008].

About half of people with NF1 have plexiform neurofibromas, but most are internal and not suspected clinically [Tonsgard et al 1998, Mautner et al 2008, Plotkin et al 2012]. Most of these tumors grow slowly if at all over periods of years, but very rapid growth can occur in benign lesions, especially in early childhood [Dombi et al 2007, Tucker et al 2009a, Nguyen et al 2012]. When symptomatic, plexiform neurofibromas can cause disfigurement and may compromise function or even jeopardize life.

Other skin findings. Juvenile xanthogranuloma and nevus anemicus are more common than expected in people with NF1 and may be useful in supporting the diagnosis in young children who do not meet the standard diagnostic criteria [Marque et al 2013, Ferrari et al 2014, Hernández-Martín et al 2015, Vaassen & Rosenbaum 2016]. Juvenile xanthogranulomas are small, tan- or orange-colored papules that may occur in clusters. Nevus anemicus is an irregularly shaped macule that is paler than surrounding skin and that does not get red when rubbed, as the skin surrounding it does.

Ocular Findings

Ocular manifestations of NF1 include optic gliomas, which may lead to blindness, Lisch nodules, and choroidal freckling. Lisch nodules are innocuous iris hamartomas that can be demonstrated on slit lamp examination in almost all adults but in fewer than half of children with NF1 younger than age five years [Ragge et al 1993]. Choroidal freckling cannot be seen on standard opthalmologic examination but can be visualized by scanning laser ophthalmoscopy with infrared or near-infrared light, infrared reflectance imaging, or optical coherence tomography [Vagge et al 2016]. The lesions, which are Schwann cell proliferations arrayed in concentric rings around an axon, occur in the majority of people with NF1 of all ages and increase in prevalence and extent with age. Infrequent ocular manifestations of NF1 include retinal vasoproliferative tumors [Hood et al 2009, Shields et al 2014] and neovascular glaucoma [Elgi et al 2010, Chiu et al 2011, Al Freihi et al 2013].

Symptomatic optic pathway gliomas in individuals with NF1 usually present before age six years with loss of visual acuity, proptosis, or strabismus, but these tumors may not become symptomatic until later in childhood or even in adulthood [Friedrich & Nuding 2016]. Symptomatic optic pathway gliomas in NF1 are frequently stable for many years or only very slowly progressive; some of these tumors even spontaneously regress [Listernick et al 2007, Shamji & Benoit 2007, Nicolin et al 2009, Sellmer et al 2018].

Neurologic Manifestations

For a discussion of peripheral nerve and central nervous system tumors see Cutaneous Features and Tumors.

Most individuals with NF1 have normal intelligence, but learning disabilities or behavioral problems occur in 50%-80% [Pride & North 2012, Lehtonen et al 2013]. Frank intellectual disability is seen in 6%-7%, a frequency about twice that in the general population [Pride & North 2012, Lehtonen et al 2013]. Features of autism spectrum disorder occur in up to 30% of children with NF1 [Garg et al 2013a, Garg et al 2013b, Walsh et al 2013, Plasschaert et al 2015, Morris et al 2016]. A variety of other learning and behavioral problems that persist into adulthood have been described [Descheemaeker et al 2013, Pride et al 2013, Granström et al 2014]. Deficits in visual-spatial performance, social competence, and attention are most commonly seen in people with NF1, but problems with motor function, executive function, memory, and language are also frequent [Pride & North 2012, Lehtonen et al 2013].

Some people with NF1 develop a diffuse polyneuropathy, often in association with multiple nerve root tumors [Drouet et al 2004, Ferner et al 2004]. Affected patients are at high risk for malignant peripheral nerve sheath tumors.

Seizures are more common in people with NF1 than in the general population and can occur at any age [Hsieh et al 2011, Ostendorf et al 2013]. The seizures are usually focal and may be associated with the presence of a brain tumor or area of infarction [Ostendorf et al 2013]. Control of focal seizures in people with NF1 may require the use of more than one antiepileptic drug or surgical removal of the affected part of the brain [Ostendorf et al 2013, Gales & Prayson 2017].

Sleep disturbance is frequent in people with NF1 [Leschziner et al 2013, Licis et al 2013, Maraña Pérez et al 2015]. Headaches, including migraine headaches, are also very common [Pinho et al 2014, Afridi et al 2015]. Pain in association with plexiform neurofibromas is also common [Kim et al 2009, Tucker et al 2009a] and must be distinguished from the pain that may be the first sign of transformation to a malignant peripheral nerve sheath tumor.

Musculoskeletal Features

Generalized osteopenia is more common than expected in people with NF1, and osteoporosis appears to be both more common and earlier in onset than in the general population [Tucker et al 2009b, Heervä et al 2012, Petramala et al 2012, Armstrong et al 2013, Heervä et al 2013]. The pathogenesis of these bony changes is not fully understood, but individuals with NF1 have often been found to have lower-than-expected serum 25-hydroxyvitamin D concentrations, elevated serum parathyroid hormone levels, and evidence of increased bone resorption [Lammert et al 2006, Brunetti-Pierri et al 2008, Stevenson et al 2008, Tucker et al 2009b, Stevenson et al 2011, Heervä et al 2012, Petramala et al 2012]. The function of both osteoblasts and osteoclasts appears to be abnormal in bone from people with NF1 [Seitz et al 2010, Kühnisch et al 2014].

Dysplasia of the long bones, most often the tibia and fibula, is an infrequent but characteristic feature of NF1 [Elefteriou et al 2009]. The lesion is congenital and is almost always unilateral. It usually presents in infancy with anteriolateral bowing of the lower leg, which is quite different from the common physiologic bowing seen in children when they begin to walk. Early recognition of tibial dysplasia permits bracing, which may prevent fracture. The initial radiographic changes are narrowing of the medullary canal with cortical thickening at the apex of the bowing [Stevenson et al 2007]. Long-bone dysplasia appears to reflect an abnormality of the bone itself and is not usually associated with adjacent neurofibromas. In contrast, sphenoid wing dysplasia and vertebral dysplasia – the other two characteristic focal bony lesions of NF1 – are associated with adjacent plexiform neurofibroma or dural ectasia (or both) [Alwan et al 2005, Arrington et al 2013, Nguyen et al 2015, Hu et al 2016].

Sphenoid wing dysplasia may be detected incidentally on cranial imaging or present as strabismus or asymmetry of the orbits. It is often static but may be progressive, occasionally disrupting the integrity of the orbit and producing pulsating enophthalmos [Friedrich et al 2010].

Scoliosis in NF1 may be of either the dystrophic or nondystrophic type [Elefteriou et al 2009]. The latter resembles common adolescent scoliosis and is not associated with vertebral anomalies. Dystrophic scoliosis occurs at a much younger age (typically age 6-8 years), is characterized by an acute angle over a short segment of the spine, and may be very rapidly progressive.

Healing of fractured or defective bone in any of these focal lesions is often unsatisfactory; treatment is frequently difficult [Pessis et al 2015, Borzunov et al 2016], and best accomplished by experienced specialists.

Children with NF1 have reduced muscle strength when compared to unaffected children of the same age, sex, and weight [Summers et al 2015].

Vascular Involvement

Hypertension is common in NF1 and may develop at any age [Friedman et al 2002, Lama et al 2004]. In most cases, the hypertension is "essential," but a characteristic NF1 vasculopathy can produce renal artery stenosis, coarctation of the aorta, or other vascular lesions associated with hypertension. A renovascular cause is often found in children with NF1 and hypertension [Fossali et al 2000, Han & Criado 2005].

Stroke is more common and often occurs at a younger age among people with NF1 than in the general population [Terry et al 2016]. NF1 vasculopathy involving major arteries or arteries of the heart or brain can have serious or even fatal consequences [Cairns & North 2008, Rea et al 2009, Stansfield et al 2012, Koss et al 2013].

• Anatomically variant stenotic or ectatic cerebral arteries and intracranial aneurysms occur more frequently in individuals with NF1 than in the general population [Rosser et al 2005, Schievink et al 2005, Bekiesińska-Figatowska et al 2014, D'Arco et al 2014].
• Cerebrovascular abnormalities in NF1 typically present as stenoses or occlusions of the internal carotid, middle cerebral, or anterior cerebral artery.
• Small telangiectatic vessels form around the stenotic area and appear as a "puff of smoke" (moya-moya) on cerebral angiography.
• Moya-moya develops about three times more often than expected in children with NF1 after cranial irradiation for primary brain tumor [Ullrich et al 2007b, Murphy et al 2015].

Cardiac Issues

Valvar pulmonic stenosis is more common in individuals with NF1 than in the general population [Lin et al 2000]. Congenital heart defects or hypertrophic cardiomyopathy may be especially frequent among persons with NF1 whole-gene deletions [Nguyen et al 2013b]. Adults with NF1 may develop pulmonary hypertension, often in association with parenchymal lung disease, another late-onset but potentially quite serious feature of NF1 [Stewart et al 2007, Zamora et al 2007, Montani et al 2011, Ennibi et al 2015]. Intracardiac neurofibromas may also occur [Nguyen et al 2013b].

Tumors

Neurofibromas are benign Schwann cell tumors that can affect virtually any nerve in the body [Stemmer-Rachamimov & Nielsen 2012]. Cutaneous neurofibromas develop in almost all people with NF1 and increase in number ‒ and very slowly in size ‒ with age. About half of people with NF1 have plexiform neurofibromas, but in most cases they are internal, and thus not apparent on clinical examination. The extent of plexiform neurofibromas seen on the surface of the body often cannot be determined by clinical examination alone. MRI is the method of choice for imaging plexiform neurofibromas (see Imaging).

Plexiform neurofibromas tend to grow in childhood and adolescence and then remain stable throughout adulthood [Dombi et al 2007, Tucker et al 2009a, Nguyen et al 2012]. Although most plexiform neurofibromas are asymptomatic, they may cause pain, grow to enormous size, cause serious disfigurement, produce overgrowth or erosion of adjacent tissue, or impinge on the function of nerves and other structures.

Malignant peripheral nerve sheath tumors are the most frequent malignant neoplasms associated with NF1, occurring in approximately 10% of affected individuals [Rasmussen et al 2001, Evans et al 2002, Walker et al 2006, Friedrich et al 2007, McCaughan et al 2007]. In comparison to the general population, malignant peripheral nerve sheath tumors tend to occur at a younger age in people with NF1, often in adolescence or early adulthood [Hagel et al 2007, McCaughan et al 2007, Valentin et al 2016]. Individuals with NF1 who have a whole-gene deletion [De Raedt et al 2003, Kluwe et al 2003, Kehrer-Sawatzki et al 2012], who have benign subcutaneous neurofibromas, or whose burden of benign internal plexiform neurofibromas is high appear to be at greater risk of developing malignant peripheral nerve sheath tumors than people with NF1 who do not have these features [Tucker et al 2005, Mautner et al 2008, Plotkin et al 2012, Nguyen et al 2014].

The most common neoplasms apart from benign neurofibromas in people with NF1 are optic nerve gliomas and brain tumors [Prada et al 2015, Blanchard et al 2016, Friedrich & Nuding 2016, Parkhurst & Abboy 2016, Sellmer et al 2017, Sellmer et al 2018]. Optic gliomas in people with NF1 are usually asymptomatic and remain so throughout life. In fact, the majority of these lesions appear to regress spontaneously – their prevalence declines from approximately 20% in young children to less than 5% in older adults with NF1 [Sellmer et al 2018]. The clinical course in patients with optic giomas tends to be milder in patients with NF1 than in those who do not have have NF1 [Mandiwanza et al 2014]. Second central nervous system gliomas occur in 17%-20% of individuals with NF1 who have optic pathway gliomas [Sharif et al 2006, Sellmer et al 2018].

Brain stem and cerebellar gliomas in individuals with NF1 may also follow a less aggressive course than in those who do not have NF1 [Ullrich et al 2007a, Sellmer et al 2017]. About 20% of people with NF1 who have one non-optic glioma have two or more of these tumors [Sellmer et al 2017]. Non-optic gliomas and malignant peripheral nerve sheath tumors within the field of treatment are substantially more common in NF1 patients with gliomas who are treated with radiotherapy [Kleinerman 2009, Madden et al 2014]. Transformation of a pilocytic astrocytoma to a more malignant brain tumor may also occur after radiatiotherapy in patients with NF1 [Krishnatry et al 2016].

Leukemia (especially juvenile chronic myelogenous leukemia) and myelodysplastic syndromes are infrequent in children with NF1 but much more common than in children without NF1. A variety of other tumors may also be seen more often than expected in individuals with NF1, including rhabdomyosarcomas [Crucis et al 2015], pheochromocytomas [Gorgel et al 2014], gastrointestinal stromal tumors [Andersson et al 2005, Takazawa et al 2005, Miettinen et al 2006, Gorgel et al 2014, Nishida et al 2016], glomus tumors [Harrison et al 2013, Kumar et al 2014], and retinal vasoproliferative tumors [Shields et al 2014]. Women with NF1 have a substantially increased risk of developing breast cancer before age 50 years [Madanikia et al 2012, Wang et al 2012, Seminog & Goldacre 2015] and of dying of breast cancer [Evans et al 2011]. People with NF1 may also be at increased risk for other cancers [Seminog & Goldacre 2013, Varan et al 2016].

Age of Onset of Manifestations

Many individuals with NF1 develop only cutaneous manifestations of the disease and Lisch nodules, but the frequency of more serious complications increases with age. Various manifestations of NF1 have different characteristic times of appearance [DeBella et al 2000b, Boulanger & Larbrisseau 2005, Williams et al 2009, Ferner et al 2011]. For example:

• Bony manifestations such as anteriolateral tibial bowing are congenital.
• Café au lait spots are often present at birth and increase in number during the first few years of life.
• Diffuse plexiform neurofibromas of the face and neck rarely appear after age one year, and diffuse plexiform neurofibromas of other parts of the body rarely develop after adolescence.
• Deep nodular plexiform neurofibromas may be seen at any age but are usually not symptomatic in childhood and often remain asymptomatic in adulthood.
• Optic gliomas develop in the first six years of life.
• The rapidly progressive (dysplastic) form of scoliosis almost always develops between ages six and ten years, although milder forms of scoliosis without vertebral anomalies typically occur during adolescence.
• Malignant peripheral nerve sheath tumors usually occur in adolescence or adulthood.

Growth

Individuals with NF1 tend to be below average in height and above average in head circumference for age [Clementi et al 1999, Szudek et al 2000a, Szudek et al 2000b, Virdis et al 2003, Karvonen et al 2013, Soucy et al 2013]. However, few individuals with NF1 have height more than 3 SD below the mean or head circumference more than 4 SD above the mean. People whose NF1 is caused by a deletion of the entire NF1 locus show a different pattern, with overgrowth (especially in height) between ages two and six years [Mautner et al 2010, Pasmant et al 2010, Kehrer-Sawatzki & Cooper 2012, Ning et al 2016]. The clinical features in some of these individuals resemble those of Weaver syndrome.

Pubertal development is usually normal, but precocious puberty may occur in children with NF1, especially in those with tumors of the optic chiasm [Virdis et al 2000, Kocova et al 2015]. Delayed puberty is also common [Virdis et al 2003].

Life Expectancy

The median life expectancy of individuals with NF1 is approximately eight years lower than in the general population [Evans et al 2011, Wilding et al 2012]. Malignancy (especially malignant peripheral nerve sheath tumors) and vasculopathy are the most important causes of early death in individuals with NF1 [Zöller et al 1995, Rasmussen et al 2001, Evans et al 2011, Masocco et al 2011].

Quality of Life

Quality of life assessments are lower in both children and adults with NF1 than in comparison groups [Vranceanu et al 2013, Merker et al 2014, Vranceanu et al 2015]. Cosmetic, medical, social, and behavioral features of the disease all may compromise the quality of life in people with NF1, and clinical depression may impair their ability to function effectively [Cohen et al 2015].

Imaging

Note: The value of performing routine head MRI scanning in individuals with NF1 at the time of diagnosis is controversial.

• Proponents state that such studies are useful in helping to establish the diagnosis in some individuals, in identifying any structural anomaly of the brain or skull, tumors, or vascular disease before it becomes clinically apparent in others, and in evaluating the context in which extracranial complications occur in still others.
• Those who oppose routine head MRI scanning point to the uncertain clinical significance of features such as UBOs ("unidentified bright objects"), the cost of such imaging, and the requirement for sedation in small children. Although clinical management should not be affected by the presence of intracranial lesions such as UBOs or optic nerve thickening in asymptomatic individuals with NF1, finding such lesions may result in regularly repeating the MRI for reassurance despite the continued absence of related symptoms, adding further to the cost as well as to the anxiety of the individual and family, without any benefit.

MRI is the method of choice for demonstrating the size and extent of plexiform neurofibromas [Mautner et al 2008, Cai et al 2009, Matsumine et al 2009, Van Meerbeeck et al 2009, Plotkin et al 2012, Hirbe & Gutmann 2014] and for monitoring their growth over time [Dombi et al 2007, Tucker et al 2009a, Nguyen et al 2012]. MRI is also useful in characterizing optic pathway gliomas, other brain tumors, structural abnormalities of the brain, and signs of cerebrovascular disease in people with NF1 [Cairns & North 2008, Rea et al 2009, Lin et al 2011, Prada et al 2015, Blanchard et al 2016, Sellmer et al 2017, Sellmer et al 2018]. MR angiography is valuable in assessing NF1 vasculopathy [D'Arco et al 2014]. Conventional radiographic studies can demonstrate the skeletal anomalies that occur in people with NF1 [Patel & Stacy 2012], but CT imaging or three-dimensional CT reconstructions may be necessary when surgical treatment of bony lesions is being planned. PET and CT/PET can help to distinguish benign and malignant peripheral nerve sheath tumors [Combemale et al 2014, Hirbe & Gutmann 2014, Salamon et al 2014, Chirindel et al 2015, Salamon et al 2015, Van Der Gucht et al 2016], but definitive differentiation can only be made by histologic examination of the tumor. CT/PET appears to be useful in guiding percutaneous biopsies of peripheral nerve sheath tumors suspected of being malignant [Brahmi et al 2015].

MRI studies have shown that people with NF1 have larger brains, on average, than people without NF1, but in NF1 gray matter volume is not correlated with IQ [Greenwood et al 2005, Margariti et al 2007, Karlsgodt et al 2012]. Enlargement of the corpus callosum is seen in some children with NF1 and has been associated with learning disabilities [Pride et al 2010, Aydin et al 2016]. More tortuosity of the optic nerve is seen on MRI in children with NF1 than in those without NF1, but optic nerve tortuosity is not associated with the occurrence of optic glioma among patients with NF1 [Ji et al 2013]. Diffusion tensor imaging has shown abnormalities of white matter microstructure, especially in the frontal lobes and corpus callosum [Ferraz-Filho et al 2012b, Karlsgodt et al 2012, Nicita et al 2014, Aydin et al 2016], and functional MRI studies have demonstrated altered connectivity in people with NF1 [Tomson et al 2015]. Individuals with NF1 also exhibit metabolic alterations in comparison to controls on magnetic resonance spectroscopy (MRS) [Nicita et al 2014, Rodrigues et al 2015].

The clinical significance of the so-called "unidentified bright objects" (UBOs) visualized on brain MRI in more than 50% of children with NF1 is uncertain [Sabol et al 2011, Friedrich & Nuding 2016, Sellmer et al 2018]. These hyperintense lesions seen on T₂-weighted imaging may occur in the optic tracts, basal ganglia, brain stem, cerebellum, or cortex, and usually show no evidence of a mass effect. Typical UBOs are not seen on T₁-weighted MRI imaging or on CT scan. UBOs show signs of intramyelinic edema on diffusion-weighted MRI [Ferraz-Filho et al 2012a, Ferraz-Filho et al 2012b, Billiet et al 2014, Ertan et al 2014] and MRS [Rodrigues et al 2015] and correspond pathologically to areas of spongiform myelinopathy [DiPaolo et al 1995]. They may disappear with age and are less common in adults than in children with NF1 [Payne et al 2014, Friedrich & Nuding 2016, Sellmer et al 2018].

The presence of UBOs does not appear to be related to the occurrence of seizures in children with NF1 [Hsieh et al 2011]. Some studies have suggested that the presence, number, volume, location, or disappearance of UBOs over time correlates with learning disabilities in children with NF1, but findings have not been consistent across investigations [Hyman et al 2007, Chabernaud et al 2009, Feldmann et al 2010, Payne et al 2014, Roy et al 2015].