Neurofibromatosis 1

Synonyms: NF1, Von Recklinghausen Disease, Von Recklinghausen's Neurofibromatosis

Friedman JM.

Publication Details


Clinical characteristics.

Neurofibromatosis 1 (NF1) is characterized by multiple café-au-lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas, and iris Lisch nodules. Learning disabilities are present in at least 50% of individuals with NF1. Less common but potentially more serious manifestations include plexiform neurofibromas, optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, and vasculopathy.


The diagnosis of NF1 is usually based on clinical findings. Heterozygous pathogenic variants in NF1 are responsible for neurofibromatosis 1. Molecular genetic testing of NF1 is rarely needed for diagnosis.


Treatment of manifestations: Referral to specialists for treatment of complications involving the eye, central or peripheral nervous system, cardiovascular system, spine, or long bones; surgical removal of disfiguring or uncomfortable discrete cutaneous or subcutaneous neurofibromas. Surgical treatment of plexiform neurofibromas is often unsatisfactory; complete surgical excision, when possible, of malignant peripheral nerve sheath tumors. Treatment of optic gliomas is generally unnecessary as they are usually asymptomatic and clinically stable. Dystrophic scoliosis often requires surgical management, whereas nondystrophic scoliosis can usually be treated conservatively.

Surveillance: Annual physical examination by a physician familiar with the disorder; annual ophthalmologic examination in children, less frequently in adults; regular developmental assessment of children; regular blood pressure monitoring; MRI for follow-up of clinically suspected intracranial tumors and other internal tumors.

Genetic counseling.

NF1 is inherited in an autosomal dominant manner. Half of affected individuals have NF1 as the result of a de novo NF1 pathogenic variant. The offspring of an affected individual are at a 50% risk of inheriting the altered NF1 gene, but the disease manifestations are extremely variable, even within a family. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant in a family is known.


Diagnosis of neurofibromatosis 1 (NF1) should be suspected in individuals who have any of the following findings and is confirmed in those who meet the diagnostic criteria for neurofibromatosis 1 (NF1) developed by the National Institutes of Health [NIH 1988]. The NIH diagnostic criteria for NF1 are met in an individual who has two or more of the following features:

  • Six or more café-au-lait macules (Figure 1) over 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals
  • Two or more neurofibromas (Figure 2) of any type or one plexiform neurofibroma (Figure 3)
  • Freckling in the axillary or inguinal regions
  • Optic glioma
  • Two or more Lisch nodules (iris hamartomas)
  • A distinctive osseous lesion such as sphenoid dysplasia or tibial pseudarthrosis
  • A first-degree relative (parent, sib, or offspring) with NF1 as defined by the above criteria
Figure 1.

Figure 1.

Café au lait macules

Figure 2.

Figure 2.


Figure 3.

Figure 3.

Plexiform neurofibroma

Adults. The NIH diagnostic criteria are both highly specific and highly sensitive in adults with NF1 [Ferner et al 2011, Ferner & Gutmann 2013].


  • Only about half of children with NF1 and no known family history of NF1 meet the NIH criteria for diagnosis by age one year; almost all do by age eight years [DeBella et al 2000a] because many features of NF1 increase in frequency with age.
  • Children who have inherited NF1 from an affected parent can usually be identified within the first year of life because diagnosis requires just one feature in addition to a positive family history. This feature is usually multiple café-au-lait spots, which develop in infancy in more than 95% of individuals with NF1 [DeBella et al 2000b, Nunley et al 2009].
  • Young children with multiple café-au-lait spots and no other NF1 features whose parents do not show signs of NF1 on careful physical and ophthalmologic examination should be strongly suspected of having NF1 and followed clinically as though they do [Nunley et al 2009].
  • A definite diagnosis of NF1 can be made in most of these children by age four years using the NIH criteria.

The diagnosis of NF1 is established in a proband who meets the NIH diagnostic criteria. Molecular genetic testing may be indicated in some individuals:

  • Molecular genetic testing is indicated for individuals in whom NF1 is suspected but who do not fulfill the NIH diagnostic criteria. This is rarely necessary after early childhood.
  • Molecular testing for NF1 may be useful in a young child with a serious tumor (e.g., optic glioma) in whom establishing a diagnosis of NF1 immediately would affect management.
  • Molecular testing of an adult with NF1 is necessary if prenatal or preimplantation genetic diagnosis in a current or future pregnancy is anticipated.
  • In some families with spinal NF1 [Burkitt Wright et al 2013] or the NF1 c.2970-2972 delAAT pathogenic variant [Upadhyaya et al 2007, Quintáns et al 2011], affected individuals may not meet the NIH diagnostic criteria, especially in childhood. Molecular testing is indicated for diagnosis of at-risk relatives in such families who do not meet the NIH diagnostic criteria.

Molecular genetic testing of NF1

  • Heterozygous loss-of-function pathogenic variants of NF1 are responsible for the disease NF1 (see Table 1), but the pathogenic variants are very heterogeneous. They include nonsense and missense single-nucleotide changes, indels, splicing variants (in ~30% of cases), whole-gene deletions (in 4%-5%), intragenic copy number changes, and other structural rearrangements [Wimmer et al 2006, Messiaen & Wimmer 2008, Valero et al 2011, Cooper & Upadhyaya 2012, Sabbagh et al 2013]. None of these pathogenic variants is frequent.
  • A multi-step variant detection protocol that identifies more than 95% of NF1 pathogenic variants in individuals fulfilling the NIH diagnostic criteria is available [Wimmer et al 2006, Messiaen & Wimmer 2008, Valero et al 2011, Sabbagh et al 2013]. This protocol involves analysis of both mRNA (cDNA) and genomic DNA, and testing for whole NF1 deletions. Because of the the variety and rarity of individual pathogenic variants found in people with NF1 and the frequency of pathogenic variants that affect splicing, these multi-step methods have much higher detection rates than methods based solely on analysis of genomic DNA (Table 1).
  • Deletion/duplication analysis. Whole-gene deletions occur in 4%-5% of individuals with NF1 [Kluwe et al 2004], and testing for whole NF1 deletions alone is sometimes performed when a "large deletion phenotype" is suspected clinically [Mautner et al 2010, Pasmant et al 2010, Kehrer-Sawatzki & Cooper 2012]. Deletion/duplication analysis may also be performed as part of a multistep variant detection protocol or as a contingent test if sequence analysis is not informative.
  • An alternative genetic testing strategy is use of a multi-gene panel that includes NF1 and other genes of interest (see Differential Diagnosis). However, with the exception of SPRED1, the clinical phenotypes associated with constitutional mutation of other genes on rasopathy, Noonan syndrome, or hereditary cancer panels are unlikely to overlap with that of NF1, and the detection frequency of pathogenic variants in NF1 on any panel performed by genomic DNA sequencing will be stubstantially lower than that obtained by targeted sequencing of NF1 cDNA within a multi-step protocol. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.
Table 1.

Table 1.

Summary of Molecular Genetic Testing Used in Neurofibromatosis 1

Clinical Characteristics

Clinical Description

The clinical manifestations of neurofibromatosis 1 (NF1) are extremely variable [Ferner et al 2007, Williams et al 2009, Ferner et al 2011, Ferner & Gutmann 2013].

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 axillia, 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 persons 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]. 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, and Lisch nodules (innocuous iris hamartomas). Symptomatic optic pathway gliomas in individuals with NF1 usually present before age six years with loss of visual acuity or proptosis, but these tumors may not become symptomatic until later in childhood or even in adulthood. Symptomatic optic pathway gliomas in NF1 are frequently stable for many years or only very slowly progressive and some of these tumors even spontaneously regress [Listernick et al 2007, Shamji & Benoit 2007, Nicolin et al 2009]. Less frequent 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].

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 and difficulties in school occur in 50%-75% [Gilboa et al 2011, Pride & North 2012, Lehtonen et al 2013, Templer et al 2013]. Frank intellectual disability is seen in 6%-7%, a frequency about twice that in the general population [Gilboa et al 2011, 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]. A variety of other learning and behavioral problems that persist into adulthood have been described [Uttner et al 2003, Pavol et al 2006, Descheemaeker et al 2013]. 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 [Gilboa et al 2011, Pride & North 2012, Lehtonen et al 2013, Templer 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]. They appear to be unrelated to the occurrence of unidentified bright objects on head MRI [Hsieh et al 2011]. Control of focal seizures in people with NF1 may require the use of more than one anti-epileptic drug or surgical removal of the affected part of the brain [Ostendorf et al 2013].

Sleep disturbance is frequent in people with NF1 [Leschziner et al 2013, Licis et al 2013]. Headaches, including migraine headaches, are more common than expected in people with NF1 [DiMario & Langshur 2000, Pinho et al 2014]. 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 be both more common and to occur at a younger age than in the general popoulation [Tucker et al 2009b, Petramala et al 2012, Heervä 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].

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, and treatment is frequently difficult. It is best accomplished by experienced specialists.

Children with NF1 have reduced muscle strength when compared to unaffected children of the same age, sex, and weight [Johnson et al 2012, Stevenson et al 2012, Hockett et al 2013].

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].

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].

  • 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" (moyamoya) on cerebral angiography.
  • Moyamoya develops about three times more often than expected in children with NF1 after cranial irradiation for primary brain tumor [Ullrich et al 2007b].
  • Anatomically variant cerebral arteries, ectatic vessels, 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].

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]. Intracardiac neurofibromas may also occur [Nguyen et al 2013b].


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 much younger age in people with NF1, often in adolescence or early adulthood, [Evans et al 2002, Friedrich et al 2007, Hagel et al 2007, McCaughan et al 2007]. Individuals with NF1 whose pathogenic variant is 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].

In children with NF1, the most common neoplasms apart from benign neurofibromas are optic nerve gliomas and brain tumors [Ferner et al 2007, Listernick et al 2007, Ullrich et al 2007a, Cassiman et al 2013]. Optic gliomas in people with NF1 are usually asymptomatic and remain so throughout life, although females are more likely than males to require treatment for symptomatic optic glioma [Diggs-Andrews et al 2014]. The course tends to be much milder than in children who do not have have NF1. Brain stem and cerebellar gliomas in individuals with NF1 may also follow a less aggressive course than in those who do not have NF1 [Vinchon et al 2000, Rosser & Packer 2002, Ullrich et al 2007a]. Second central nervous system gliomas subsequently occur in at least 20% of individuals with NF1 who had optic pathway gliomas diagnosed in childhood [Sharif et al 2006]. 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].

Leukemia (especially juvenile chronic myelogenous leukemia and myelodysplastic syndromes) is infrequent in children with NF1 but much more common than in children without NF1. A variety of other tumors may also be seen in individuals with NF1, including gastrointestinal stromal tumors [Andersson et al 2005, Takazawa et al 2005, Guillaud et al 2006, Miettinen et al 2006, Kramer et al 2007] and retinal vasoproliferative tumors [Shields et al 2014]. Women with NF1 have a substantially increased risk of developing breast cancer before age 50 years [Walker et al 2006, Sharif et al 2007, Madanikia et al 2012, Wang et al 2012] and of dying of breast cancer [Evans et al 2011]. People with NF1 may also be at increased risk for many other common cancers [Seminog & Goldacre 2013].

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-aul-ait 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.


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. In contrast, persons with NF1 whose pathogenic variant is 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]. The clinical features in some of these children 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]. 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 [Birch & Friedman 2012, Vranceanu et al 2013]. Cosmetic, medical, behavioral, and social features of the disease all may compromise the quality of life in people with NF1.


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 brain tumors, structural abnormalities and the brain, and signs of cerebrovascular disease [Cairns & North 2008, Rea et al 2009, Lin et al 2011] in people with NF1. 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 [Ferner et al 2008, Matsumine et al 2009, Warbey et al 2009, Tsai et al 2012, Meany et al 2013, Salamon et al 2013, Hirbe & Gutmann 2014], but definitive differentiation can only be made by histologic examination of the tumor.

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]. Diffusion tensor imaging has shown abnormalities of white matter microstructure, especially in the frontal lobes [Ferraz-Filho et al 2012b, 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]. 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].

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 [DeBella et al 2000a, Lopes Ferraz Filho et al 2008, Sabol et al 2011]. 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 abnormal myelin structure on diffusion-weighted MRI [Ferraz-Filho et al 2012a, Ferraz-Filho et al 2012b, Billiet et al 2014] 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 [Gill et al 2006, Payne et al 2014].

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 the findings have not been consistent across investigations [Hyman et al 2007, Chabernaud et al 2009, Feldmann et al 2010, Payne et al 2014].

Genotype-Phenotype Correlations

NF1 is characterized by extreme clinical variability, not only between unrelated individuals and among affected individuals within a single family but even within a single person with NF1 at different times in life. Only two clear correlations have been observed between particular mutant NF1 alleles and consistent clinical phenotypes:

  • A deletion of the whole NF1 gene is associated with large numbers and early appearance of cutaneous neurofibromas, more frequent and more severe cognitive abnormalities, and somatic overgrowth, large hands and feet, and dysmorphic facial features [Mautner et al 2010, Pasmant et al 2010, Kehrer-Sawatzki & Cooper 2012].
  • A 3-bp in-frame deletion of exon 17 (c.2970-2972 delAAT) [NF Consortium nomenclature; exon 22 of NCBI nomenclature] is associated with typical pigmentary features of NF1 but no cutaneous or surface plexiform neurofibromas [Upadhyaya et al 2007].

Persons with NF1 (including those with NF1/Noonan syndrome or Watson syndrome phenotypes) who also have pulmonic stenosis appear to have non-truncating NF1 pathogenic variants more frequently than the truncating variants that are found more often in other persons with NF1 [Ben-Shachar et al 2013].

The consistent familial transmission of NF1 variants such as Watson syndrome (multiple café-au-lait spots, pulmonic stenosis, and intellectual disability) [Allanson et al 1991, Tassabehji et al 1993] and familial spinal neurofibromatosis [Upadhyaya et al 2009, Pizzuti et al 2011, Burkitt Wright et al 2013] also indicates that allelic heterogeneity plays a role in the clinical variability of NF1. Statistical analysis of the NF1 phenotype within and between families suggests that the NF1 mutated allele itself accounts for only a small fraction of phenotypic variation [Sabbagh et al 2009, Sabbagh et al 2013]. Differences in expression of the benign NF1 allele may account for some of the phenotypic variability [Jentarra et al 2012]. Statistical analysis of clinical features in affected families suggests that modifying genes at other loci influence many aspects of the NF1 phenotype [Pasmant et al 2012].

The extreme clinical variability of NF1 suggests that random events are important in determining the phenotype of affected individuals. Evidence in support of this interpretation is provided by the occurrence of acquired "second hit" variants or loss of heterozygosity at the NF1 locus in some neurofibromas, malignant peripheral nerve sheath tumors, pheochromocytomas, astrocytomas, gastrointestinal stromal tumors, myeloid malignancies, mandibular giant cell granulomas and glomus tumors from patients with NF1 [Upadhyaya et al 2012]. NF1 loss of heterozygosity has also been observed in melanocytes grown from café-au-lait spots [Maertens et al 2007, De Schepper et al 2008] and tissue associated with tibial pseudarthrosis in some cases [Stevenson et al 2006b, Lee et al 2012].

It seems likely that the clinical variability of NF1 results from a combination of genetic, non-genetic, and stochastic factors. Such complexity and the diversity of constitutional NF1 pathogenic variants that occur in this disease will continue to make genotype-phenotype correlation difficult.


Penetrance is virtually complete after childhood.


NF1 was previously referred to as peripheral neurofibromatosis, to distinguish it from NF2 (central neurofibromatosis) – although central nervous system involvement may also occur in NF1.

"Neurofibromatosis" without further specification is sometimes used in the literature to refer to NF1, but this usage is confusing because other authors employ the term "neurofibromatosis" to designate a group of conditions that includes NF2, schwannomatosis, and other clinically similar disorders as well as NF1.


NF1 is one of the most common dominantly inherited genetic disorders, occurring with an incidence at birth of approximately one in 3000 individuals [Lammert et al 2005, Evans et al 2010].

Almost half of all affected individuals have a de novo pathogenic variant. The variant rate for NF1 (~1:10,000) is among the highest known for any gene in humans. The cause of the unusually high variant rate is unknown.

Differential Diagnosis

More than 100 genetic conditions and multiple congenital anomaly syndromes that include café-au-lait spots or other individual features of neurofibromatosis 1 (NF1) have been described, but few of these disorders are ever confused with NF1.

Conditions most frequently confused with NF1

  • Legius syndrome, a dominantly inherited condition that includes multiple café-au-lait spots, axillary freckling, macrocephaly and, in some individuals, facial features that resemble Noonan syndrome [Brems et al 2012] caused by heterozygous pathogenic variants in SPRED1. Affected individuals may meet the diagnostic criteria for NF1, but Lisch nodules, neurofibromas, and central nervous system tumors do not usually occur. Distinguising Legius syndrome from NF1 is sometimes impossible on the basis of physical features alone in a young child because the multiple cutaneous neurofibromas and Lisch nodules that characterize most patients with NF1 do not usually arise until later in childhood or adolescence. Examination of the parents for signs of Legius syndrome or NF1 can often make it possible to distinguish the two conditions, but in sporadic cases reevaluation of the patient after adolescence or molecular testing may be necessary to establish the diagnosis.
  • Constitutive mismatch repair deficiency associated with homozygosity or compound heterozygosity for a pathogenic variant in one of the genes causing Lynch syndrome [Wimmer 2012]. The cutaneous phenotype is remarkably similar to NF1, and affected individuals may meet the NIH diagnostic criteria for NF1. However, individuals homozygous for pathogenic variants associated with Lynch syndrome usually develop tumors that are typical of Lynch syndrome but with a younger age of onset than seen in Lynch syndrome heterozygotes. This condition is distinguishable from NF1 in that the parents are often consanguineous and one or both parents often have clinical findings and/or a family history of Lynch syndrome. Typically, neither parent has clinical findings of NF1. A pathogenic variant in NF1 is usually not demonstrable in the blood of these patients.
  • Piebald trait (OMIM) (areas of cutaneous pigmentation and depigmentation with hyperpigmented borders of the unpigmented areas, white forelock). Some individuals with this condition meet the diagnostic criteria for NF1 [Stevens et al 2012].
  • Neurofibromatosis 2 (bilateral vestibular schwannomas, schwannomas of other cranial and peripheral nerves, cutaneous schwannomas, meningiomas, juvenile posterior subcapsular cataract). NF2 is genetically and clinically distinct from NF1.
  • Schwannomatosis (OMIM) (multiple schwannomas of cranial, spinal or peripheral nerves, usually without vestibular, ocular or cutaneous features of NF2) [Merker et al 2012]
  • Multiple café au lait spots (an autosomal dominant trait without other features of neurofibromatosis) (OMIM). The families described have not been tested for SPRED1 pathogenic variants; thus it is not known if this condition is distinct from Legius syndrome, which has a similar phenotype.
  • LEOPARD syndrome (multiple lentigines, ocular hypertelorism, deafness, congenital heart disease)
  • McCune-Albright syndrome (large café-au-lait spots with irregular margins, polyostotic fibrous dysplasia)
  • Noonan syndrome (short stature, congenital heart defect, neck webbing, and characteristic facies)
  • Infantile myofibrosis (OMIM, OMIM) (multiple tumors of the skin, subcutaneous tissues, skeletal muscle, bones, and viscera)
  • Proteus syndrome (hamartomatous overgrowth of multiple tissues, connective tissue nevi, epidermal nevi, hyperostoses)
  • Multiple orbital neurofibromas, painful peripheral nerve tumors, distinctive face, and marfanoid habitus [Babovic-Vuksanovic et al 2012]


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with neurofibromatosis 1 (NF1), the following evaluations are recommended:

  • Personal medical history with particular attention to features of NF1
  • Physical examination with particular attention to the skin, skeleton, cardiovascular system, and neurologic systems
  • Ophthalmologic evaluation including slit lamp examination of the irides
  • Developmental assessment in children
  • Other studies as indicated on the basis of clinically apparent signs or symptoms
  • Clinical genetics consultation

In addition, a family history with particular attention to features of NF1 should be obtained, and physical examinations and ophthalmologic examinations (including slit lamp exams) should be performed on both parents to determine if the condition in the affected individual was inherited or occurred de novo. This determination is necessary for genetic counseling and may help identify patients who have a condition that is not caused by mutation of NF1, such as Legius syndrome or constitutive mismatch repair deficiency (see Differential Diagnosis).

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, 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.

Treatment of Manifestations

Patient management guidelines for NF1 have been put forward by the American Academy of Pediatrics [Hersh 2008], the National Society of Genetic Counselors [Radtke et al 2007], and various expert groups [Ferner et al 2007, Williams et al 2009, Ferner & Gutmann 2013].

Individuals with NF1 who have abnormalities involving the eye, central or peripheral nervous system, spine or long bones, or cardiovascular system should be referred to an appropriate specialist for treatment.

Discrete cutaneous or subcutaneous neurofibromas that are disfiguring or in inconvenient locations (e.g., at belt or collar lines) can be removed surgically, or, if small, by laser or electrocautery.

  • Surgical treatment of plexiform neurofibromas is often unsatisfactory because of their intimate involvement with nerves and their tendency to grow back at the site of removal [Fadda et al 2007, Serletis et al 2007, Prada et al 2012, Nguyen et al 2013a].
  • In one small series in which surgical removal of superficial plexiform neurofibromas was undertaken in children while the tumors were still relatively small, it was possible to resect the neurofibromas without producing any neurologic deficit [Friedrich et al 2005].
  • Radiotherapy is contraindicated because of the risk of inducing malignant peripheral nerve sheath tumors in these genetically predisposed individuals [Evans et al 2002].
  • A 54% reduction in the volume of a plexiform neurofibroma has been reported in an individual with NF1 who received two cycles of carboplatin chemotherapy for a coincident seminoma [Hummel et al 2011].
  • A phase II clinical trial reported apparent benefit in approximately 25% of patients with large plexiform neurofibromas treated with imatinib, a tyrosine kinase inhibitor [Robertson et al 2012]. Further studies are in progress.

Pain, development of a neurologic deficit, or enlargement of a preexisting plexiform neurofibroma may signal a malignant peripheral nerve sheath tumor and require immediate evaluation [Valeyrie-Allanore et al 2005]. Examination by MRI, PET, or PET/CT [Ferner et al 2008, Matsumine et al 2009, Warbey et al 2009, Salamon et al 2013] is useful in distinguishing benign and malignant peripheral nerve sheath tumors, but definitive differentiation can only be made by histologic examination of the tumor. Complete surgical excision, when possible, is the only treatment that offers the possibility of cure of malignant peripheral nerve sheath tumors [Friedrich et al 2007, Dunn et al 2013]. Adjuvant chemotherapy or radiotherapy is sometimes used as well and appears to have benefitted some (but not most) patients with NF1 [Gottfried et al 2006, Chaudhary & Borker 2012, Zehou et al 2013].

Most optic pathway gliomas found on MRI in people with NF1 are asymptomatic and do not require treatment [Segal et al 2010, Oh et al 2011, Cassiman et al 2013]. Chemotherapy is the treatment of choice for progressive optic pathway gliomas in children with NF1, although the results are mixed [Rosenfeld et al 2010, Ardern-Holmes & North 2011, Fisher et al 2012]. Surgical treatment of optic nerve glioma is usually reserved for cosmetic palliation in a blind eye, and radiotherapy is usually avoided because of the risk of inducing malignancy or moyamoya in the exposed field [Evans et al 2002, Ullrich et al 2007a].

The natural history of brain stem and cerebellar astrocytomas in individuals with NF1 should be taken into consideration in deciding on management of such tumors [Vinchon et al 2000, Rosser & Packer 2002, Ullrich et al 2007a].

Dystrophic scoliosis in children with NF1 often requires surgical management, which may be complex and difficult [Shen et al 2005, Tsirikos et al 2005, Stoker et al 2012, Kawabata et al 2013]. Nondystrophic scoliosis in persons with NF1 can be treated in a manner similar to idiopathic scoliosis.

Surgical treatment of tibial pseudarthrosis is difficult and often unsatisfactory [Stevenson et al 2013].


Patient management guidelines for NF1 have been put forward by the American Academy of Pediatrics [Hersh 2008], the National Society of Genetic Counselors [Radtke et al 2007], and various expert groups [Ferner et al 2007, Williams et al 2009, Ferner & Gutmann 2013].

The following are recommended:

  • Annual physical examination by a physician who is familiar with the individual and with the disease
  • Annual ophthalmologic examination in early childhood, less frequent examination in older children and adults
  • Regular developmental assessment by screening questionnaire (in childhood)
  • Regular blood pressure monitoring
  • Other studies (e.g., MRI) only as indicated on the basis of clinically apparent signs or symptoms
  • Monitoring of those who have abnormalities of the central nervous system, skeletal system, or cardiovascular system by an appropriate specialist

Agents/Circumstances to Avoid

No limitations are necessary for most individuals with NF1. Limitations may be required if certain particular features such as tibial dysplasia or dysplastic scoliosis are present; in these instances the limitation is determined by the feature, not by the presence of NF1 itself.

Radiotherapy of individuals with NF1 appears to be associated with a high risk of developing malignant peripheral nerve sheath tumors within the field of treatment [Evans et al 2002, Sharif et al 2006].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Although most pregnancies in women with NF1 are normal, serious complications can occur [Chetty et al 2011, Terry et al 2013].

  • Many women with NF1 experience a rapid increase in the number and size of neurofibromas during pregnancy.
  • Hypertension may first become symptomatic or, if preexisting, may be greatly exacerbated during pregnancy.
  • Large pelvic or genital neurofibromas can complicate delivery, and cesarean section appears to be necessary more often in pregnant women with NF1 than in other women.

Therapies Under Investigation

Various medical treatments for plexiform and spinal neurofibromas are being evaluated in clinical trials [Ferner & Gutmann 2013, Lin & Gutmann 2013]. Preliminary studies suggest that sirolimus, an mTOR inhibitor, may be useful in treating pain associated with plexiform neurofibromas [Hua et al 2014] (see Note).

Radiofrequency therapy has shown promise for treatment of facial diffuse plexiform neurofibromas and café-au-lait spots in small clinical series [Baujat et al 2006, Yoshida et al 2007].

Controlled trials of several therapeutic approaches to malignant peripheral nerve sheath tumors are available to individuals with NF1 [Ferner & Gutmann 2013, Lin & Gutmann 2013] (see Note).

Several controlled trials for treatment of optic pathway gliomas are available to individuals with NF1 [Schnur 2012, Ferner & Gutmann 2013, Lin & Gutmann 2013] (see Note).

Note: NIH has a list of current clinical trials for NF1.


Hormonal contraception appears not to stimulate the growth of neurofibromas in women with NF1 [Lammert et al 2006].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Neurofibromatosis 1 (NF1) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Approximately 50% of individuals with NF1 have an affected parent and 50% have the altered gene as the result of a de novo NF1 pathogenic variant.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include medical history and physical examination with particular attention to dermal and other features of NF1. In addition, an ophthalmologic examination (including slit lamp examination) should be performed on both parents to look for Lisch nodules or other ophthalmologic signs of NF1.

Note: The family history may appear to be negative because of failure to recognize NF1 in family members or early death of a parent before the recognition of signs or symptoms.

Sibs of a proband

  • The risk to the sibs of the proband depends on whether one of the proband's parents has NF1.
  • If a parent is affected, the risk to the sibs is 50%.
  • If neither parent of an individual with NF1 meets the clinical diagnostic criteria for NF1 after careful medical history, physical examination, and ophthalmologic examination, the risk to the sibs of the affected individual of having NF1 is low but greater than that of the general population because of the possibility of germline mosaicism. Note: Germline mosaicism for an NF1 pathogenic variant has been demonstrated in an apparently unaffected man who had two children with typical NF1 [Lázaro et al 1995] and in a woman with segmental NF who had a child with typical manifestations of NF1 [Consoli et al 2005].

Offspring of a proband

  • Each child of an individual with NF1 has a 50% chance of inheriting the NF1 pathogenic variant.
  • Penetrance is 100%; thus, a child who inherits an NF1 pathogenic variant will develop features of NF1, but the disease may be considerably more (or less) severe in an affected child than in his or her affected parent.

Other family members of a proband. If a proband’s parent is affected, other members of his or her family may be at risk.

Related Genetic Counseling Issues

Possibility of multiple de novo pathogenic variants in a single family. Upadhyaya et al [2003] reported the occurrence of three different NF1 pathogenic variants in one family and advised caution in assuming that the same pathogenic variant is present in all members of an affected family. Two different NF1 pathogenic variants have been reported in another family [Klose et al 1999].

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal or preimplantation genetic diagnosis is before pregnancy.
  • Genetic counseling (including discussion of potential risks to offspring and reproductive options) should be offered to young adults who are affected or at risk.

Prenatal Testing

Molecular genetic testing. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed [van Minkelen et al 2014].

Ultrasound examination. Prenatal diagnosis of exceptionally severe NF1 by prenatal ultrasound examination has been reported [McEwing et al 2006], but ultrasound examination is unlikely to be informative in most cases.

Requests for prenatal testing for conditions which (like NF1) can have a wide range of severity and age of onset are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) of NF1 has been reported [Spits et al 2005, Altarescu et al 2006, Vanneste et al 2009, Chen et al 2011] and may be an option for some families in which the NF1 pathogenic variant has been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Table A.

Neurofibromatosis 1: Genes and Databases

Table B.

Table B.

OMIM Entries for Neurofibromatosis 1 (View All in OMIM)

Gene structure. NF1 is large (~350 kilobases and 60 exons) and codes for at least three alternatively spliced transcripts [Upadhyaya & Cooper 2012]. NF1 is unusual in that one of its introns contains coding sequences for at least three other genes. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 1000 different pathogenic variants in NF1 have been identified. Most pathogenic variants are unique to a particular family. Many pathogenic variants have been observed repeatedly, but none has been found in more than a few percent of families studied. Many different kinds of pathogenic variatns have been observed, including stop variants, amino acid substitutions, deletions (which may involve only one or a few base pairs, multiple exons, or the entire gene), insertions, intronic changes affecting splicing, alterations of the 3' untranslated region of the gene, and gross chromosome rearrangements. Most of the germline pathogenic variants described in individuals with NF1 appear to cause severe truncation of the gene product, often by altering mRNA splicing.

Table 2.

Table 2.

NF1 Pathogenic Variants Discussed in This GeneReview

Normal gene product. The protein product, neurofibromin, has a calculated molecular mass of approximately 327 kd. The function of neurofibromin is not fully understood. It activates ras GTPase, thereby controlling cellular proliferation and acting as a tumor suppressor [Gottfried et al 2010, Upadhyaya & Cooper 2012]. Neurofibromin has other functions as well, including regulation of adenylyl-cyclase activity and intracellular cyclic-AMP generation.

Abnormal gene product. NF1 results from loss-of-function variants in NF1 [Upadhyaya & Cooper 2012].

Cancer and Benign Tumors

Several kinds of tumors that occur with increased frequency among persons with NF1 may exhibit somatic (but not germline) NF1 variants of one or both alleles in individuals who do not have clinical features of NF1. Examples of NF1 variants in such sporadic NF1-associated tumors occurring in the absence of any other findings of this syndrome include malignant peripheral nerve sheath tumors [Bottillo et al 2009], pheochromocytomas [Vicha et al 2013], juvenile myelomonocytic leukemia [Yoshimi et al 2010, Sakaguchi et al 2013], gliomas [Purow & Schiff 2009], and breast cancer [Cancer Genome Atlas Network 2012].

Somatic variants of NF1 may also be found in lung adenocarcinomas, ovarian carcinomas, colorectal carcinomas, melanomas, and adult acute myeloid leukemia, all of which are rare in individuals with NF1 [Laycock-van Spyk et al 2011, Patil & Chamberlain 2012, Yap et al 2014].


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Suggested Reading

  • Gutmann DH, Collins FS. Neurofibromatosis 1. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, eds. The Online Metabolic and Molecular Bases of Inherited Disease (Scriver’s OMMBID). Chap 39. New York, NY: McGraw-Hill. Available online.

  • Kaufmann D, ed. Neurofibromatoses. Monographs in Human Genetics. Vol 16. Basel, Switzerland: Karger; 2008.

  • Korf BR, Rubenstein AE. Neurofibromatosis: A Handbook for Patients, Families, and Health Care Professionals. 2 ed. New York, NY: Thieme Medical Publishers; 2005.

Chapter Notes

Revision History

  • 4 September 2014 (me) Comprehensive update posted live
  • 3 May 2012 (me) Comprehensive update posted live
  • 2 June 2009 (me) Comprehensive update posted live
  • 31 January 2007 (me) Comprehensive update posted to live Web site
  • 5 October 2004 (me) Comprehensive update posted to live Web site
  • 30 September 2002 (me) Comprehensive update posted to live Web site
  • 2 October 1998 (pb) Review posted to live Web site
  • Spring 1996 (jmf) Original submission