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, Associate Clinical Director, Pappas Center for Neuro-Oncology, Family Center for Neurofibromatosis, Massachusetts General Hospital; Instructor of Neurology, Harvard Medical School, for assistance in preparation of this report.
Neurofibromatosis 1 (NF1), also called von Recklinghausen's disease, is a genetic disorder characterized by the development of multiple noncancerous (benign) tumors of nerves and skin (neurofibromas) and areas of abnormal skin color (pigmentation). Areas of abnormal skin pigmentation typically include 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 over time.
At birth or early childhood, affected individuals may have relatively large, benign tumors that consist of bundles of nerves and other tissue (plexiform neurofibromas). 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.
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. Associated symptoms and findings may vary greatly in range and severity from person to person, even within the same family. Most people with NF1 have normal intelligence but learning disabilities appear in about 50% of children with NF1.
NF1 is caused by changes (mutations) 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) mutations of the gene that occur for unknown reasons. Such individuals do not inherit NF1 from their parents, but rather they are the first in their family with the disorder. In others, NF1 is inherited as an autosomal dominant trait.
According to the National Institutes of Health (NIH) Consensus Conference in 1987, a clinical diagnosis of NF1 may be made if patients demonstrate at least two of the following: (1) Six or more café-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) Abnormal clumps of pigment on the colored portion of the eye (Lisch nodules); (4) Certain abnormalities of bone development in the head (sphenoid wing dysplasia) or abnormal bowing of bones (pseudoarthrosis); (5) Two or more neurofibromas of any type or one plexiform neurofibroma; (6) An affected parent, sibling, or child with confirmed NF1.
Symptoms of NF1 usually begin during childhood, and a definite diagnosis can often be made by four 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, and the rate of progression of this disorder is not predictable. However, a majority of patients (approximately 60%) are described as having a “mild” form of the condition.
Often the first sign of NF1 is the appearance of multiple brown spots on the skin (café-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, or less discrete 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, weight loss, night sweats, and require urgent evaluation and treatment.
Approximately 15% of people with NF1 develop brain tumors (gliomas), which nearly always develop during childhood. These frequently develop on the nerves of the eye (optic gliomas), and may affect vision or potentially lead to blindness. Additionally, a variety of other tumors may develop in patients with NF1, including gastrointestinal stromal tumors (GIST). In women with NF1, there is a 3.5-fold increased risk of developing breast cancer and a five-fold increased risk of developing breast cancer before the age of 50 years of age.
Orthopedic problems may develop with NF1, including curvature of the spine (scoliosis), abnormal cranial bone growth (sphenoid wing dysplasia), or a condition characterized by loss of bone tissue, fractures, and abnormal healing and bowing 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 “precocious puberty” 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.
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 (i.e. autosomal dominant disease). NF1 does not skip generations. Sporadic or random mutations 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, a remarkably large gene, has been mapped to chromosome 17q11, and has one of the highest known mutation rates (1:10,000) for any human gene. The causes of this high rate of mutation are still under investigation, and may be due (in part) to the large size of the gene leading to a greater chance of random error during cellular growth.
The NF1 gene regulates (encodes for) the production of neurofibromin, a protein that functions to prevent the development of tumors (tumor suppressor). Mutations 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 neurofibromin’s tumor suppressor activity and cause a tumor in that region.
Several different mutations of the NF1 gene have been identified in individuals with the disorder (i.e., deletions, insertions, point mutations). Investigators have determined that some severely affected individuals may have a deletion of the entire NF1 gene as well as deletion of material from other adjacent genes (contiguous genes), potentially contributing to the wide variability of symptoms and findings in those with the disorder.
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 mutation (genetic mosaicism), and so signs and symptoms of segmental NF1 often appear in only a portion of the body. The NF1 mutation 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 two or more of the following criteria are present:
Six or more cafe-au-lait spots 1.5 centimeters (cm) or larger in post-pubertal individuals, 0.5 cm or larger in pre-pubertal individuals
Two or more neurofibromas of any type or one or more “plexiform” neurofibroma
Freckling under the arms (axillary) or in the groin area (inguinal)
Non-malignant tumor of the optic nerve (optic glioma)
Two or more Lisch nodules in the iris of the eyes (iris hamartomas)
Specific bone lesions including abnormal development of the sphenoid bone of the skull (sphenoid dysplasia) or thinning, fractures, and bowing of long bones (pseudoarthrosis)
A parent, sibling, or child (first degree relative) with NF1
Diagnosis of NF1 is usually based on clinical findings. Laboratory tests are available to diagnose individuals where NF1 may be suspected. Some of the skin findings (i.e., café-au-lait spots) are not always easily visible and may require use of an ultraviolet light to identify. Molecular genetic testing for mutations in the NF1 gene can be used for diagnosis prior to the development of symptoms in many cases.
People with NF1 may undergo surgery to remove particularly troublesome or disfiguring tumors, depending on their size and location. Laser or electrocautery treatment is also 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 and depends on tumor type and location. Physical therapy may be beneficial for some people. A variety of orthopedic devices may help to improve mobility in some cases. 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. Childhood patients are recommended to have annual ophthalmologic exams, as well as regular 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 quantitative monitoring of internal tumors.
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 Resources 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]
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 Children’s 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 Children’s 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.
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Friedman JM, Gutman DH, MacCollin M, Riccardi VM. Neurofibromatosis: Phenotype, Natural History, and Pathogenesis (3rd Edition). Baltimore, MD and London, England: Johns Hopkins University Press; 1999.
Abramowicz A, Gos M. Neurofibromin in neurofibromatosis type 1 – 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.
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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.
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Schnur RE. Type I neurofibromatosis: a geno-oculo-dermatologic update. Curr Opin Ophthalmol. 2012 Sep; 23(5): 364-72.
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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.
Friedman JM. Neurofibromatosis 1. 1998 Oct 2 [Updated 2014 Sep 4]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1109/ Accessed January 3, 2017.
McKusick VA, Ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Neurofibromatosis, Type I; NF1. Entry Number; 162200.Available at http://omim.org/entry/162200 : Last Edit Date 11/15/2016. Accessed January 3, 2017.
Pinson S. Neurofibromatosis type I. Orphanet. Available at: www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=636 Last update: July 2014. Accessed January 3, 2017.
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