Neurofibromatosis Type 1
- Author: David T Hsieh, MD, FAAP; Chief Editor: Amy Kao, MD more...
Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder that is characterized by cutaneous findings, most notably café-au-lait spots and axillary freckling (see the images below), by skeletal dysplasias, and by the growth of both benign and malignant nervous system tumors, most notably benign neurofibromas.
Signs and symptoms
Signs and symptoms of NF1 can vary widely from patient to patient. The earliest clinical finding usually seen in children with NF1 is multiple café-au-lait spots. These may be present at birth or may appear over time, frequently increasing in size and number throughout childhood.
Axillary or inguinal freckles are rarely present at birth, but appear during childhood through adolescence. Subcutaneous or cutaneous neurofibromas are seen rarely in young children but appear over time in older children, adolescents, and adults.
Other signs and symptoms may include the following:
High blood pressure
Optic nerve tumors
Learning disabilities; Attention deficit hyperactivity disorder; Autism spectrum disorder
Larger than average head size
See Clinical Presentation for more detail.
Clinical diagnosis requires the presence of at least 2 of 7 criteria to confirm the presence of NF1. Many of these signs do not appear until later childhood or adolescence; thus, confirming the diagnosis often is delayed despite a suspicion of NF1. The 7 clinical criteria used to diagnose NF1 are as follows, in the absence of alternative diagnoses:
Six or more café-au-lait spots or hyperpigmented macules =5 mm in diameter in prepubertal children and 15 mm postpubertal
Axillary or inguinal freckles (>2 freckles)
Two or more typical neurofibromas or one plexiform neurofibroma
Optic nerve glioma
Two or more iris hamartomas (Lisch nodules), often identified only through slit-lamp examination by an ophthalmologist
Sphenoid dysplasia or typical long-bone abnormalities such as pseudarthrosis
First-degree relative (eg, mother, father, sister, brother) with NF1
See Workup for more detail.
There is no cure for neurofibromatosis. Patients should be routinely monitored for complications. Annual examinations should include the following:
Assessment of skin to look for new neurofibromas or progression of existing lesions
Check of blood pressure
Evaluation of growth and development
A complete eye exam
Evaluation of skeletal changes and abnormalities
Assessment of learning development
Chemotherapy, radiation therapy, or both may be used to treat cancerous tumors, but with the avoidance of radiation therapy when possible, due to the incurred increased risk of secondary malignancies.
Surgery can be used to remove tumors that cause pain or a loss of function. Neurofibromas that press on vital structures, obstruct vision, or grow rapidly deserve immediate attention.
Orthopedic intervention is indicated for rapidly progressive scoliosis and for some severe bony defects.
See Treatment and Medication for more detail.
Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder that commonly is associated with cutaneous, neurologic, and orthopedic manifestations. It is the most frequent of the so-called hamartoses.
NF type 1 (NF1) is differentiated from central NF or NF type 2 in which patients demonstrate a relative paucity of cutaneous findings but have a high incidence of meningiomas and acoustic neuromas (which are frequently bilateral). NF1 has a lower incidence of CNS tumors than NF2. However, complications of NF1 can include visual loss secondary to optic nerve gliomas, spinal cord tumors, scoliosis, vascular lesions, and long-bone abnormalities.
The manifestations of NF1 result from a mutation in or deletion of the NF1 gene. The gene product neurofibromin serves as a tumor suppressor; decreased production of this protein results in the myriad of clinical features.
The estimated incidence of NF1 is 1 in 3000, but the actual frequency may be higher because of less than complete ascertainment of mildly affected individuals. Approximately half of affected individuals represent first cases in the family as a result of a new genetic event or mutation.
Life Expectancy in NF1 is approximately 8 years lower than the general population.
Lifetime risks for both benign and malignant tumors are increased in NF1-affected individuals.
Cutaneous or subcutaneous neurofibromas, optic nerve gliomas, dumbbell-shaped spinal cord tumors, and brain tumors, particularly gliomas, represent some of the well-recognized nerve-related neoplasms.
Adolescence for both genders may precipitate the development of subcutaneous and cutaneous neurofibromas. Increase in the size of existing neurofibromas and the appearance of new neurofibromas during pregnancy is a frequent observation in women with NF1.
Plexiform neurofibromas, generally larger, more diffuse, and locally invasive are seen in more than one fourth of patients with NF1 and can present difficult management decisions. The management of close surveillance versus intervention is often debated, with the recognition that complete resection of a plexiform neurofibroma without residual functional deficits is rarely possible. On the other hand, debulking or partial resection of plexiform neurofibromas may be undertaken for cosmetic purposes or if progressive functional consequences are anticipated.
Gliomas in patients with NF1 tend to be lower grade and have a more favorable prognosis than in patients without NF1, with pilocytic astrocytomas and low-grade astrocytomas (subtype intermediate) being most common. However, diffusely infiltrating astrocytomas are also seen in a subset of patients and need to be managed accordingly.
Malignant peripheral nerve sheath tumors (MPNSTs) and neurosarcomas are not uncommon in adolescents and adults with NF1, with an approximate lifetime risk of 10%. These malignancies frequently arise from large plexiform neurofibromas or extensive peripheral nerve lesions. MPNSTs in patients with NF1 carry a poorer prognosis than in patients without this condition; tumor volume is an independent prognostic indicator.
More than 1% of patients with NF1 develop an indolent symmetric sensory axonal neuropathy. However, some cases of polyneuropathy occur in association with diffuse nerve root lesions or MPNSTs.
Gastrointestinal stromal tumors (GIST), often multiple with a predilection for the proximal small bowel, may be seen in patients with NF1. Therefore, there should be a high index of suspicion for a GIST in a patient who presents with GI bleeding or intestinal obstruction. Gene mutations typically seen in sporadic GISTs leading to malignant transformation are rarely identified in the GISTs removed from patients with NF1. Instead, activation of the Ras-MAPK pathway and loss of heterozygosity of specific chromosomal regions may underlie the development of GISTs in patients with NF1.
Learning disabilities with or without attention deficit hyperactivity disorder (ADHD) are seen in approximately 40% of NF1-affected individuals. A much smaller percentage experience more significant cognitive difficulties such as mild or moderate mental retardation. Furthermore, a recent population based study reported a prevalence of autism spectrum disorder in 30%.
Scoliosis in NF1 is often mild, but a subset of children younger than 10 years develop a more rapidly progressive form of scoliosis that requires aggressive intervention.
Bony abnormalities may be clinically silent, with radiographic evidence of long bone intramedullary fibrosis, cortical thinning, or vertebral dural ectasias often found incidentally. Sphenoid bone dysplasia and long-bone bowing or pseudarthrosis are common features of NF1. In the past, congenital tibial pseudarthrosis led to below-the-knee amputation; however, recent advances in orthopedic management with limb-sparing procedures have decreased the need for such drastic procedures.
Osteoporosis with statistically significant decreases in bone mineral density can be identified in individuals with NF1, perhaps even as early as childhood. Whereas a number of metabolic pathways impacting bone metabolism have been implicated in the pathogenesis of bone abnormalities in people with NF, studies in children and teens with NF have provided evidence for increased rates of bone resorption as a likely cause for osteopenia.
Emerging evidence shows that vitamin D deficiency combined with a higher than normal bone turnover contributes to decreased bone mineral density (BMD) in patients with NF1. One study looking at adults with NF1 (mean age, early 40s), showed that 50% had osteopenia and 19% had frank osteoporosis. Males were more likely than females to have reduced BMD; 56% of patients had a low 25-hydroxy-vitamin D while 34% had elevated parathyroid hormone. Judicious vitamin D supplementation may prove beneficial for patients with NF1 who have vitamin D deficiency or evidence of osteopenia.
Hypertension in NF1 can be seen at any age, with many adults with NF1 manifesting the usual essential form of hypertension. However, any person with NF1 and high blood pressure must be evaluated carefully for 2 alternative causes of hypertension (see Prognosis).
Pheochromocytomas are not rare (< 5%) in NF1 and can cause severe, fluctuating hypertension.
Vascular stenosis (ie, renal artery stenosis secondary to fibromuscular dysplasia) also may result in hypertension that may not respond well to standard pharmacologic management.
Other vascular lesions, especially in the central nervous system, such as vascular ectasias, stenoses, moyamoya disease, and aneurysms, occur more frequently in patients with NF1. Rarely, coronary artery aneurysms are identified in symptomatic or even asymptomatic individuals with NF1.
Short stature is common in NF1; affected individuals are often shorter than their unaffected siblings.
Macrocephaly is common in NF1 and should not cause undo alarm if present in affected infants or young children, unless serial head circumference measurements confirm the rapid crossing of percentiles.
Chiari type 1 malformations are seen with increased frequency in the NF1 population.
Puberty usually occurs at a normal age, but precocious puberty with growth acceleration may occur in a small number of individuals. When precocious puberty is present, the patient must be evaluated for a chiasmal lesion causing disruption of the hypothalamic-pituitary axis.
Race-, sex-, and age-related demographics
All races and ethnic backgrounds are affected equally. However, evidence indicates that the risk for optic nerve glioma is lower in African Americans than in Caucasians and Hispanics.
Males and females are affected equally with this autosomal dominant condition. However, one study showed that female patients with NF1-associated optic glioma were twice as likely to undergo brain magnetic resonance imaging for visual symptoms and three times more likely to require treatment for visual decline than their male counterparts.
Scoliosis may be especially severe in young girls compared to their male counterparts.
Although the genetic change causing NF1 is present at conception, clinical manifestations may appear slowly over many years.
Diagnosis often is made earlier in children born to an NF1-affected parent; the clinical criteria for diagnosis are fulfilled more easily, and the clinician may be more attuned to this possible diagnostic concern.
If an at-risk individual reaches the age of 10 years without meeting the diagnostic criteria for NF1, he or she is unlikely to be affected.
Wilding A, Ingham SL, Lalloo F, et al. Life expectancy in hereditary cancer predisposing diseases: an observational study. J Med Genet. 2012. 49:264–9. [Medline].
Dugoff L, Sujansky E. Neurofibromatosis type 1 and pregnancy. Am J Med Genet. 1996 Dec 2. 66(1):7-10. [Medline].
Darrigo LG Jr, Geller M, Bonalumi Filho A, et al. Prevalence of plexiform neurofibroma in children and adolescents with type I neurofibromatosis. J Pediatr (Rio J). 2007 Nov-Dec. 83(6):571-3. [Medline].
Rodriguez FJ, Perry A, Gutmann DH, et al. Gliomas in neurofibromatosis type 1: a clinicopathologic study of 100 patients. J Neuropathol Exp Neurol. 2008 Mar. 67(3):240-9. [Medline].
Porter DE, Prasad V, Foster L, Dall GF, Birch R, Grimer RJ. Survival in Malignant Peripheral Nerve Sheath Tumours: A Comparison between Sporadic and Neurofibromatosis Type 1-Associated Tumours. Sarcoma. 2009. 2009:756395. [Medline]. [Full Text].
Basile U, Cavallaro G, Polistena A, Giustini S, Orlando G, Cotesta D. Gastrointestinal and Retroperitoneal Manifestations of Type 1 Neurofibromatosis. J Gastrointest Surg. 2009 Jun 3. [Medline].
Hegyi L, Thway K, Newton R, Osin P, Nerurkar A, Hayes AJ. Malignant myoepithelioma arising in adenomyoepithelioma of the breast and coincident multiple gastrointestinal stromal tumours in a patient with neurofibromatosis type 1. J Clin Pathol. 2009 Jul. 62(7):653-5. [Medline].
Yamamoto H, Tobo T, Nakamori M, Imamura M, Kojima A, Oda Y. Neurofibromatosis type 1-related gastrointestinal stromal tumors: a special reference to loss of heterozygosity at 14q and 22q. J Cancer Res Clin Oncol. 2009 Jun. 135(6):791-8. [Medline].
Garg S, Green J, Leadbitter K, Emsley R, Lehtonen A, Evans DG, et al. Neurofibromatosis Type 1 and Autism Spectrum Disorder. Pediatrics. 2013 Nov 4. [Medline].
Brunetti-Pierri N, Doty SB, Hicks J, et al. Generalized metabolic bone disease in Neurofibromatosis type I. Mol Genet Metab. 2008 May. 94(1):105-11. [Medline].
Stevenson DA, Schwarz EL, Viskochil DH, et al. Evidence of increased bone resorption in neurofibromatosis type 1 using urinary pyridinium crosslink analysis. Pediatr Res. 2008 Jun. 63(6):697-701. [Medline].
Seitz S, Schnabel C, Busse B, Schmidt HU, Beil FT, Friedrich RE, et al. High bone turnover and accumulation of osteoid in patients with neurofibromatosis 1. Osteoporos Int. 2010 Jan. 21(1):119-27. [Medline].
Tucker T, Schnabel C, Hartmann M, Friedrich RE, Frieling I, Kruse HP. Bone health and fracture rate in individuals with neurofibromatosis 1 (NF1). J Med Genet. 2009 Apr. 46(4):259-65. [Medline].
Smith A, Araoz PA, Kirsch J. Coronary arterial aneurysms in neurofibromatosis 1: case report and review of the literature. J Thorac Imaging. 2009 May. 24(2):129-31. [Medline].
Diggs-Andrews KA, Brown JA, Gianino SM, et al. Sex is a major determinant of neuronal dysfunction in neurofibromatosis type 1. Ann Neurol. 2014. 75:309-16. [Medline].
Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA. 1997. 278:51-7. [Medline].
Listernick R, Ferner RE, Liu, GT, Gutmann DH. Optic pathway gliomas in neurofibromatosis-1: Controversies and recommendations. Ann Neurol. 2007. 61:189-98. [Medline].
Spurlock G, Bennett E, Chuzhanova N, Thomas N, Jim HP, Side L. SPRED1 mutations (Legius syndrome): another clinically useful genotype for dissecting the neurofibromatosis type 1 phenotype. J Med Genet. 2009 Jul. 46(7):431-7. [Medline].
Shah KN. The diagnostic and clinical significance of café-au-lait macules. Pediatr Clin North Am. 2010. 57:1131-53. [Medline].
Karagiannis A, Mikhailidis DP, Athyros VG, et al. Pheochromocytoma: an update on genetics and management. Endocr Relat Cancer. 2007 Dec. 14(4):935-56. [Medline].
Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: which test is best?. JAMA. 2002 Mar 20. 287(11):1427-34. [Medline].
Prada CE, Hufnagel RB, Hummel TR, et al. The use of magnetic resonance imaging screening for optic pathway gliomas in children with neurofibromatosis type 1. J Pediatr. 2015. 167:851-6. [Medline].
Tucker T, Friedman JM, Friedrich RE, Wenzel R, Fünsterer C, Mautner VF. Longitudinal study of neurofibromatosis 1 associated plexiform neurofibromas. J Med Genet. 2009 Feb. 46(2):81-5. [Medline].
Iannicelli E, Rossi G, Almberger M, et al. Integrated imaging in peripheral nerve lesions in type 1 neurofibromatosis. Radiol Med (Torino). 2002 Apr. 103(4):332-43. [Medline].
Matsumine A, Kusuzaki K, Nakamura T, Nakazora S, Niimi R, Matsubara T, et al. Differentiation between neurofibromas and malignant peripheral nerve sheath tumors in neurofibromatosis 1 evaluated by MRI. J Cancer Res Clin Oncol. 2009 Jul. 135(7):891-900. [Medline].
Pacak K, Eisenhofer G, Ahlman H, et al. Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005. Nat Clin Pract Endocrinol Metab. 2007 Feb. 3(2):92-102. [Medline].
Benz MR, Tchekmedyian N, Eilber FC, Federman N, Czernin J, Tap WD. Utilization of positron emission tomography in the management of patients with sarcoma. Curr Opin Oncol. 2009 Jul. 21(4):345-51. [Medline].
Levine E, Huntrakoon M, Wetzel LH. Malignant nerve-sheath neoplasms in neurofibromatosis: distinction from benign tumors by using imaging techniques. AJR Am J Roentgenol. 1987 Nov. 149(5):1059-64. [Medline].
Wojtkowiak JW, Fouad F, LaLonde DT, et al. Induction of apoptosis in neurofibromatosis type 1 malignant peripheral nerve sheath tumor cell lines by a combination of novel farnesyl transferase inhibitors and lovastatin. J Pharmacol Exp Ther. 2008 Jul. 326(1):1-11. [Medline].
Ambrosini G, Cheema HS, Seelman S, et al. Sorafenib inhibits growth and mitogen-activated protein kinase signaling in malignant peripheral nerve sheath cells. Mol Cancer Ther. 2008 Apr. 7(4):890-6. [Medline].
Johansson G, Mahller YY, Collins MH, et al. Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors. Mol Cancer Ther. 2008 May. 7(5):1237-45. [Medline].
Slomiany MG, Dai L, Bomar PA, Knackstedt TJ, Kranc DA, Tolliver L, et al. Abrogating drug resistance in malignant peripheral nerve sheath tumors by disrupting hyaluronan-CD44 interactions with small hyaluronan oligosaccharides. Cancer Res. 2009 Jun 15. 69(12):4992-8. [Medline].
Hari Kumar KV, Shaikh A, Sandhu AS, Prusty P. Neurofibromatosis 1 with pheochromocytoma. Indian J Endocrinol Metab. 2011 Oct. 15 Suppl 4:S406-8. [Medline]. [Full Text].
Gerszten PC, Burton SA, Ozhasoglu C, et al. Radiosurgery for benign intradural spinal tumors. Neurosurgery. 2008 Apr. 62(4):887-95; discussion 895-6. [Medline].
Bravo EL, Tagle R. Pheochromocytoma: state-of-the-art and future prospects. Endocr Rev. 2003 Aug. 24(4):539-53. [Medline].
AAP Committee on Genetics. Health supervision for children with neurofibromatosis. American Academy of Pediatrics Committee on Genetics. Pediatrics. 1995 Aug. 96(2 Pt 1):368-72. [Medline].
Chander S, Westphal SM, Zak IT, et al. Retroperitoneal malignant peripheral nerve sheath tumor: evaluation with serial FDG-PET. Clin Nucl Med. 2004 Jul. 29(7):415-8. [Medline].
DeClue JE, Cohen BD, Lowy DR. Identification and characterization of the neurofibromatosis type 1 protein product. Proc Natl Acad Sci U S A. 1991 Nov 15. 88(22):9914-8. [Medline].
Deliganis AV, Geyer JR, Berger MS. Prognostic significance of type 1 neurofibromatosis (von Recklinghausen Disease) in childhood optic glioma. Neurosurgery. 1996 Jun. 38(6):1114-8; discussion 1118-9. [Medline].
Denckla MB, Hofman K, Mazzocco MM, et al. Relationship between T2-weighted hyperintensities (unidentified bright objects) and lower IQs in children with neurofibromatosis-1. Am J Med Genet. 1996 Feb 16. 67(1):98-102. [Medline].
Drouet A, Wolkenstein P, Lefaucheur JP, et al. Neurofibromatosis 1-associated neuropathies: a reappraisal. Brain. 2004 Sep. 127:1993-2009. [Medline].
Evans DG, Baser ME, McGaughran J, et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002 May. 39(5):311-4. [Medline].
Ferner RE, Hughes RA, Hall SM, et al. Neurofibromatous neuropathy in neurofibromatosis 1 (NF1). J Med Genet. 2004 Nov. 41(11):837-41. [Medline].
Gutmann DH, Collins FS. The neurofibromatosis type 1 gene and its protein product, neurofibromin. Neuron. 1993 Mar. 10(3):335-43. [Medline].
Habiby R, Silverman B, Listernick R, et al. Precocious puberty in children with neurofibromatosis type 1. J Pediatr. 1995 Mar. 126(3):364-7. [Medline].
Hughes RJ, Scoble JE, Reidy JF. Renal angioplasty in non-atheromatous renal artery stenosis: technical results and clinical outcome in 43 patients. Cardiovasc Intervent Radiol. 2004 Sep-Oct. 27(5):435-40. [Medline].
Karadimas P, Hatzispasou E, Bouzas EA. Retinal vascular abnormalities in neurofibromatosis type 1. J Neuroophthalmol. 2003 Dec. 23(4):274-5. [Medline].
Korf BR. Malignancy in neurofibromatosis type 1. Oncologist. 2000. 5(6):477-85. [Medline].
Levy AD, Patel N, Abbott RM, et al. Gastrointestinal stromal tumors in patients with neurofibromatosis: imaging features with clinicopathologic correlation. AJR Am J Roentgenol. 2004 Dec. 183(6):1629-36. [Medline].
Listernick R, Ferner RE, Piersall L, et al. Late-onset optic pathway tumors in children with neurofibromatosis 1. Neurology. 2004 Nov 23. 63(10):1944-6. [Medline].
Nakakura S, Shiraki K, Yasunari T, et al. Quantification and anatomic distribution of choroidal abnormalities in patients with type I neurofibromatosis. Graefes Arch Clin Exp Ophthalmol. 2005 Oct. 243(10):980-4. [Medline].
Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol. 1988 May. 45(5):575-8. [Medline].
North KN, Riccardi V, Samango-Sprouse C, et al. Cognitive function and academic performance in neurofibromatosis. 1: consensus statement from the NF1 Cognitive Disorders Task Force. Neurology. 1997 Apr. 48(4):1121-7. [Medline].
Riccardi VM. Neurofibromatosis. Phenotype, Natural History and Pathogenesis. 2nd ed. Johns Hopkins University Press; 1992.
Scott RM, Smith JL, Robertson RL, Madsen JR, Soriano SG, Rockoff MA. Long-term outcome in children with moyamoya syndrome after cranial revascularization by pial synangiosis. J Neurosurg. 2004 Feb. 100(2 Suppl Pediatrics):142-9. [Medline].
Solomon J, Warren K, Dombi E, et al. Automated detection and volume measurement of plexiform neurofibromas in neurofibromatosis 1 using magnetic resonance imaging. Comput Med Imaging Graph. 2004 Jul. 28(5):257-65. [Medline].
Zacharia TT, Jaramillo D, Poussaint TY, et al. MR imaging of abdominopelvic involvement in neurofibromatosis type 1: a review of 43 patients. Pediatr Radiol. 2005 Mar. 35(3):317-22. [Medline].
Zöller M, Rembeck B, Akesson HO, et al. Life expectancy, mortality and prognostic factors in neurofibromatosis type 1. A twelve-year follow-up of an epidemiological study in Göteborg, Sweden. Acta Derm Venereol. 1995 Mar. 75(2):136-40. [Medline].