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Last updated: April 25, 2022
Years published: 1985, 1986, 1987, 1988, 1989, 1990, 1991, 1992, 1993, 1994, 1995, 1996, 1997, 1998, 1999, 2000, 2002, 2005, 2017, 2022
NORD gratefully acknowledges Madeline Zupan, NORD Editorial Intern from the University of Notre Dame, Kristina Bundra, Pharm D, NORD Editorial Intern, and Justin T. Jordan, MD, MPH, FAAN, Director of the Family Center for Neurofibromatosis and Clinical Director of the Pappas Center for Neuro-Oncology at Massachusetts General Hospital; Assistant Professor of Neurology, Harvard Medical School, for assistance in preparation of this report.
Summary
Neurofibromatosis 1 (NF1), historically called von Recklinghausenโs disease, is a genetic disorder characterized by increased risk of developing noncancerous (benign) and cancerous (malignant) tumors, as well as various other physical and neurological manifestations. The most prevalent manifestations of the disease are multiple tumors of nerves and skin (neurofibromas), as well as areas of abnormal skin color (pigmentation). The abnormal skin color typically includes pale tan or light brown discolorations (cafe-au-lait spots), freckling in atypical locations such as under the arms (axillary region) or in the groin (inguinal region). Such abnormalities of skin pigmentation are often evident by one year of age and tend to increase in size and number through childhood.
At birth or early childhood, affected individuals may have relatively large, benign tumors that consist of bundles of nerves and other tissue (plexiform neurofibromas). It is estimated that up to 50% of patients with NF1 may have at least one plexiform neurofibroma. Individuals with NF1 may also develop benign nodules on the colored regions of the eyes (Lisch nodules), or tumors in the nerves of the visual pathway (optic pathway gliomas). More rarely, affected individuals may develop certain malignant (cancerous) tumors. For instance, the risk of breast cancer is significantly increased in women with NF1 compared to the general population, especially during the age range of 30-40 years old. Patients also carry 8-13% lifetime risk of developing a tumor known as malignant peripheral nerve sheath tumor (MPNST), often occurring due to cancerous transformation of a pre-existing benign plexiform neurofibroma. Gastrointestinal stromal tumor (GIST) is a tumor arising from the small intestine that may be either benign or malignant. Pheochromocytoma, which is a tumor on the adrenal gland, may increase blood pressure and pulse. Gliomas, tumors arising within the brain, may occur during childhood (especially in the vision pathway, known as optic pathway gliomas), or later in adulthood.
NF1 may also be characterized by an unusually large head size (macrocephaly) and relatively short stature. Additional abnormalities may also be present, such as episodes of uncontrolled electrical activity in the brain (seizures); learning disabilities and attention deficits; speech difficulties; abnormally increased activity (hyperactivity); and skeletal malformations, including progressive curvature of the spine (scoliosis), bowing of the lower legs (pseudoarthrosis), and improper development of certain bones. There is also an increased risk of vascular abnormalities with NF1, including a narrowing of the arteries to the kidneys (renal artery stenosis), which may cause early high blood pressure or aneurysms. Certain types of strokes may be more common with NF1. Associated symptoms and findings may vary greatly in range and severity from person to person, even within the same family. Learning disabilities appear in more than 50% of children with NF1.
NF1 is caused by changes (pathogenic variants) in a gene called NF1, which is found on chromosome 17. This gene regulates the production of a protein known as neurofibromin, which is thought to function as a tumor suppressor. In about 50 percent of individuals with NF1, the disorder results from spontaneous (sporadic) changes in the NF1 gene that occur for unknown reasons. These individuals do not inherit NF1 from their parents, but rather they are the first in their family with the disorder. In other patients, NF1 is inherited in an autosomal dominant pattern, which means that each child of an affected parent carries a 50% risk of inheriting the disease. NF1 does not skip generations.
The diagnostic criteria for NF1 were updated by international consensus in 2021. Based on the new criteria, an individual who does not have a parent diagnosed with NF1 will meet clinical diagnostic criteria for NF1 if they demonstrate at least two of the following:
(1) Six or more cafรฉ-au-lait spots of at least 5 millimeters [mm] in size (before puberty) or 15 mm in size (after puberty)
(2) Freckling in the underarms (axillary) or groin (inguinal) regions
(3) Two or more neurofibromas of any type, or one plexiform neurofibroma
(4) Optic pathway glioma
(5) Two or more abnormal clumps of pigment on the colored portion of the eye (Lisch nodules) or two or more abnormalities in the back of the eye (choroidal abnormalities) seen with special imaging of the eye
(6) Certain abnormalities of bone development in the head (sphenoid wing dysplasia) or a bowing of the tibia bone in the leg or other long bones (pseudoarthrosis)
(7) A pathogenic variant in the NF1 gene in normal tissue (such as blood, saliva) meeting certain technical criteria.
Notably, for individuals born to a parent with NF1 (meeting diagnostic criteria above), only one of the above criteria must also be met to reach the diagnosis of NF1.
Symptoms of NF1 usually begin during childhood, and a definite diagnosis can often be made by three years of age or younger, depending on the circumstance. The disorder is progressive across the lifetime. In some cases, NF1 symptoms have been described to worsen during puberty, pregnancy or when hormonal changes occur, though this correlation remains incompletely understood. The range and severity of NF1 symptoms varies greatly among affected individuals โ even within the same family, and the rate of progression of this disorder is not predictable. However, a majority of patients (approximately 60%) are described as having a โmildโ form of the condition.
Often the first sign of NF1 is the appearance of multiple brown spots on the skin (cafรฉ-au-lait macules) or freckling in the underarm (axillary) or groin (inguinal) regions, which may occur as early as birth or infancy. Lisch nodules may also be present early in life, and are highly suggestive of an NF1 diagnosis, as they occur in approximately 97% of affected individuals.
Multiple noncancerous (benign) tumors (neurofibromas) develop in NF1 along the linings of the nerves (sheath) under the skin or in deeper areas of the body. Neurofibromas may form in any organ in the body. Skin (cutaneous) neurofibromas, under the skin (subcutaneous) neurofibromas or more diffuse neurofibromas (plexiform neurofibromas) may cause disfigurement. Occasionally, tumors may develop in the brain, on the nerves exiting the brain and/or on the spinal cord. The total number of neurofibromas in an adult may range from a few to hundreds or even thousands, and the number of these tumors tends to increase with age. Pain may occur from an affected peripheral nerve, or as a result of regional mass effect on adjacent structures. In 8-15% of affected individuals, neurofibromas may transform to become cancerous (malignant peripheral nerve sheath tumors), which are associated with pain, rapid tumor growth or new neurological symptoms, and require urgent evaluation and treatment.
Approximately 15% of people with NF1 develop brain tumors (gliomas), which most commonly develop during childhood. These frequently develop on in the visual structures of the brain (optic pathway gliomas) and may affect vision, cause premature onset of puberty (precocious puberty) or increased head size (macrocephaly). Additionally, a variety of other tumors may develop in patients with NF1, including gastrointestinal stromal tumors (GIST). In women with NF1, there is a 4 to 11-fold increased risk of developing breast cancer compared to the general population before age 50, though this risk is the highest between 30 and 40 years old. Further, even after diagnosis of breast cancer on one side, there is a high risk of developing a second breast cancer in the opposite (contralateral) breast.
Orthopedic problems may develop with NF1, including curvature of the spine (scoliosis), abnormal cranial bone growth (sphenoid wing dysplasia) or a condition characterized by bowing and fracturing of weight-bearing long bones (pseudoarthrosis). Additionally, disorders of bone density (osteopenia and osteoporosis) are more common in people with NF1 than in the general population. The process by which these conditions develop is not fully understood, but has been associated with decreased activated vitamin D levels, increased parathyroid hormone levels, and increased markers of bone breakdown. People with NF1 tend to be below average in height, below average in muscle strength and above average in head size for age.
High blood pressure (hypertension) is seen with greater frequency in the NF1 population than the general population. While the cause for this is not certain, some cases may not directly relate to NF1, but rather to associated changes in the blood vessels leading to the kidneys (renal artery stenosis). More rarely, patients with NF1 are at risk of developing tumors of the adrenal gland (pheochromocytoma), which may cause severely elevated blood pressure without treatment.
Sexual development may be delayed or may occur early (precocious puberty) in individuals with NF1. (For more information on this disorder, choose โprecocious pubertyโ as your search term in the Rare Disease Database.) In addition, over 50% of individuals with NF1 experience learning disabilities such as attention deficit hyperactivity disorder (ADHD). Seizures may also occur. Other symptoms include headache, numbness and/or weakness.
In the localized form of NF1, known as segmental neurofibromatosis, abnormal pigmentation and/or tumors may be limited to one area of the body, and there may be an overall milder manifestation of the disease.
In about 50% of individuals with NF1, the disorder is inherited from a parent. Only one parent need be affected to cause a child to have NF1 (autosomal dominant inheritance). NF1 does not skip generations. Sporadic or random pathogenic variants in the gene responsible for NF1 account for the remaining 50% of cases and occur when a child has NF1 but neither parent does.
The NF1 gene regulates (encodes for) the production of neurofibromin, a protein that functions to prevent the development of tumors (tumor suppressor). Mutations (pathogenic variants) in the NF1 gene lead to the production of a nonfunctional version of neurofibromin or decreased expression of neurofibromin, thereby dysregulating cellular growth and division. Whereas there are two functional copies of every gene in the human body, and only one copy of the NF1 gene is mutated in all tissues due to its autosomal dominant nature, a second mutation event is necessary in a given cell to completely lose neurofibrominโs tumor suppressor activity and cause a tumor in that region.
Many different pathogenic variants of the NF1 gene have been identified in individuals with the disorder. In general, there is little correlation between a particular pathogenic variant and particular disease manifestations or severity, as evidenced by the wide disease variation within families that have the same NF1 gene change. It is hypothesized that disease variability relates to variability in other genes (modifier genes) and to environmental factors.
A more localized form of NF1 (segmental NF1) is caused by a genetic change in the NF1 gene that is not inherited, but rather occurs sporadically during embryo development (somatic mutation). Only a portion of the cells in the body have the disease-causing NF1 pathogenic variant (genetic mosaicism), so signs and symptoms of segmental NF1 may appear in only a portion of the body or may be overall reduced in severity and distribution. The NF1 pathogenic variant responsible for a segmental NF1 case may be inherited by offspring and cause full NF1; the risk of this transmission is not well understood, and likely depends on the distribution of mutated cells in the parent.
NF1 is a rare disorder that affects males and females in equal numbers. NF1 affects all races and ethnic groups equally and is estimated to occur in 1 in 2,500 to 3,000 births.
The diagnosis of NF1 is usually made during the first decade of life, based on characteristic skin freckling, cafe-au-lait spots, optic glioma and/or pseudoarthrosis. NF1 should be suspected if any one of the criteria are present and diagnosed if the following are met:
โข For an individual who does not have a parent diagnosed with NF1, two or more of the items listed below are required for a diagnosis of NF1. For individuals born to a parent with NF1, only one finding in the below list is required to meet diagnostic criteria for NF1
โข Six or more cafรฉ-au-lait spots of at least 5 millimeters [mm] in size (before puberty) or 15 mm in size (after puberty)
โข Freckling in the underarms (axillary) or groin (inguinal) regions
โข Two or more neurofibromas of any type, or one plexiform neurofibroma
โข A tumor of the visual structures of the brain or eye nerves (optic pathway glioma)
โข Two or more abnormal clumps of pigment on the colored portion of the eye (Lisch nodules) or two or more abnormalities in the back of the eye (choroidal abnormalities) seen with special imaging of the eye
โข Certain abnormalities of bone development in the head (sphenoid wing dysplasia) or a bowing of the tibia bone in the leg or other long bones (pseudoarthrosis)
โข A pathogenic variant in the NF1 gene in normal tissue (such as blood, saliva) with an allele fraction of 50% (meaning half of the copies of NF1 in the body are impacted by the pathogenic variant)
Diagnosis of NF1 is usually based on clinical findings, although increasingly genetic testing is used to support the evaluation and/or for family planning purposes. Some of the skin findings (i.e., cafรฉ-au-lait spots) are not always easily visible and may require use of an ultraviolet light (Woodโs lamp) to identify.
Treatment
For cutaneous, subcutaneous, and deep neurofibromas, surveillance is often the preferred strategy due to the benign nature of the lesions. If treatment is required, patients may undergo surgery to remove particularly troublesome or disfiguring tumors, depending on their size and location. Laser or electrocautery treatment may also be an option for smaller skin neurofibromas. Radiation therapy, chemotherapy or both treatments may be used by some clinicians to treat NF1-associated tumors, though their role is less clear as the risks are often considered to outweigh the benefits in such cases. Clinical trials are ongoing to better understand these options.
For plexiform neurofibromas, complete surgical removal is generally not possible due to the diffuse nature of the lesions. In April 2020, Koselugo (selumetinib) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of NF1-associated plexiform neurofibromas that are disfiguring or inoperable in children 2 years and older. This drug is a kinase inhibitor, meaning it functions by blocking a key enzyme that promotes cellular growth, and according to published data this medication results in shrinking plexiform tumors in up to 70% of patients.
Physical therapy may be beneficial for some people, based on difficulties arising from tumors or bone abnormalities. A variety of orthopedic devices may help to improve mobility in some patients. Other treatment is symptomatic and supportive. For example, in patients who develop scoliosis, a brace may be necessary to prevent progression.
Regular monitoring is important for managing the disease. Annual physical exams are recommended for all patients, in addition to blood pressure screening and frequent eye exams. Children with NF1 are recommended to have annual ophthalmologic exams, as well as regular checks of head circumference and developmental assessments. Advanced imaging (MRI, PET, or PET/CT) may be advised to monitor internal tumors depending on location and symptoms. Whole-body MRI is under investigation as a tool for monitoring of internal tumors. Annual breast cancer screening (either by mammography or breast MRI) is recommended to begin at age 30 for females with NF1.
Further monitoring of specific system abnormalities may be necessary. Patients should consult an appropriate specialist if they have abnormalities of the central nervous system, skeletal system, cardiovascular system or eyes.
Genetic counseling is recommended for people with NF1 and their families. For clinical facilities that treat people with neurofibromatosis, please refer to the Organizations section of this report.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For more information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
The Childrenโs Tumor Foundation launched a Neurofibromatosis (NF) Registry in 2012. The purpose of this registry is to find people who may be eligible for clinical trials or other research studies being conducted in the field of NF, and to determine the commonality of specific NF characteristics. Please go to www.nfregistry.org for more information.
The Childrenโs Tumor Foundation supports the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) initiative in an effort to develop new standardized response criteria for determining treatment response with neurofibromatosis 1, neurofibromatosis 2 and schwannomatosis. The purpose of this effort is to better compare treatment efficacy in clinical trials.
For more information about this collaboration contact: Dr. Scott R. Plotkin at [email protected].
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
TEXTBOOKS
Korf BR. Neurofibromatosis: A Handbook for Patients, Families, and Health Care Professionals, 2nd ed. Thieme. 2005.
Short MP. Neurofibromatosis Type 1. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:563-64.
JOURNALARTICLES
Legius E, et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genetics in Medicine. 2021; 23:1506โ1513. https://www.nature.com/articles/s41436-021-01170-5
Ly KI, Blakeley JO. The diagnosis and management of neurofibromatosis type 1. Med Clin North Am. 2019 Nov;103(6):1035-1054. https://pubmed.ncbi.nlm.nih.gov/31582003/
Miller DT, et al. Health supervision for children with neurofibromatosis type 1. Pediatrics. 2019 May;143(5):e20190660. https://publications.aap.org/pediatrics/article/143/5/e20190660/37168/Health-Supervision-for-Children-With
Stewart DR, et al. Care of adults with neurofibromatosis type 1: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2018 Jul;20(7):671-682. https://www.nature.com/articles/gim201828.epdf?author_access_token=iEIdSMKoseD1GJgsPVBwMdRgN0jAjWel9jnR3ZoTv0NtGxP-tdc55QiaUfq15TwmsoZTCgkAIkTxcaP62d96ZEv1KiKznUV2J6cABL1eFDqmEDBSI7up7q6wJv9X5KXz
Abramowicz A, Gos M. Neurofibromin in neurofibromatosis type 1 โ mutations in NF1gene as a cause of disease. Dev Period Med. 2014 Jul-Sep; 18(3): 297-306.
Tadini G, Milani D, Menni F, Pezzani L, Sabatini C, Esposito S. It is time to change the neurofibromatosis 1 diagnostic criteria? Eur J Intern Med. 2014 July; 25(6): 506-10.
Thway K, Fisher C. Malignant peripheral nerve sheath tumor: pathology and genetics. Ann Diagn Pathol. 2014 Apr; 18(2): 109-16.
Cassiman C. Kegius E. Spileers W, et al. Ophthalmological assessment of children with neurofibromatosis type 1. Eur J Pediatr. 2013 Oct; 172(10): 1327-33.
Ferner Re, Gutmann DH. Neurofibromatosis type 1(NF1): diagnosis and management. Handb Clin Neurol. 2013; 115: 939-55.
Templer AK, Titus JB, Gutmann DH. A neuropsychological perspective on attention problems in neurofibromatosis type 1. J Atten Disord. 2013 Aug; 17(6): 489-96.
Vranceanu AM, Merker VL, Park E, et al. Quality of life among adult patients with neurofibromatosis 1, neurofibromatosis 2 and schwannomatosis: a systematic review of the literature. J Neurooncol. 2013 Sep; 114(3): 257-62.
Patel NB, Stacy GS. Musculoskeletal manifestations of neurofibromatosis type 1. AJR Am J Roentgenol. 2012 Jul; 199(1): 99-106.
Schnur RE. Type I neurofibromatosis: a geno-oculo-dermatologic update. Curr Opin Ophthalmol. 2012 Sep; 23(5): 364-72.
Jouhilahti EM, Peltonen S, Heape AM, Peltonen J. The pathoetiology of neurofibromatosis 1. AM J Pathol. 2011 May; 178(5) 1932-9.
Cohen R, Shuper A. Developmental manifestation in children with neurofibromatosis type 1. Harefuah. 2010 Jan; 149(1): 49-52, 61.
Feldman DS, Jordan C, Fonseca L. Orthopaedic manifestations of neurofibromatosis type 1. J Am Acad Orthop Surg. 2010 Jun; 18(6): 346-57.
Jett K, Friedman JM. Clinical and genetic aspect of neurofibromatosis 1. Genet Med. 2010 Jan; 12(1): 1-11.
Albers AC. Gutmann DH. Gliomas in patients with neurofibromatosis type 1. Expert Rev Neurother. 2009 Apr; 9(4): 535-9.
Elefterious F, Kolanczyk M, Schindeler A, et al. Skeletal abnormalities in neurofibromatosis type 1: approaches to therapeutic options. Am J Med Genet A. 2009 Oct; 149A(10): 2327-38.
Lu-Emerson C, Plotkin SR. The neurofibromatoses. Part I: NF1. Rev Neurol Dis. 2009 Spring; 6(2): 47-53.
Parsons CM, Canter RJ, Khatri VP. Surgical management of neurofibromatosis. Surg Oncol Clin N Am. 2009 Jan; 18(1): 175-96.
INTERNET
Friedman JM. Neurofibromatosis 1. 1998 Oct 2 [Updated 2019 Jun 6]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1109/ Accessed April 20, 2022.
McKusick VA, Ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Neurofibromatosis, Type I; NF1. Entry Number; 162200.Available at https://omim.org/entry/162200 : Last Edit Date 02/22/2022. Accessed April 20, 2022.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
View reportGeneReviews has an article on this condition covering diagnosis, management, and inheritance. Each article is written by one or more experts on the specific disease and is reviewed by other specialists. The article contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. The GeneReviews database is managed by the University of Washington.
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