Neurofibromatosis Type 1 (NF1)
Neurofibromatosis Type 1 (NF1)
National Organization for Rare Disorders, Inc.
It is possible that the main title of the report Neurofibromatosis Type 1 (NF1) is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.
- neurofibroma, multiple
- neurofibromatosis-pheochromocytoma-duodenal carcinoid syndrome
- peripheral neurofibromatosis
- Recklinghausen's phakomatosis
- Von Recklinghausen's disease
- Von Recklinghausen's neurofibromatosis
Related Disorders List
Information on the following diseases can be found in the Related Disorders section of this report:
- Neurofibromatosis Type 2 (NF2)
- McCune-Albright syndrome
- Proteus Syndrome
- Tuberous Sclerosis
- Noonan Syndrome
- Neurofibromatosis-Noonan Syndrome
- Watson Syndrome
Neurofibromatosis type 1 (NF1), also called von Recklinghausen's disease, is a rare genetic disorder characterized by the development of multiple noncancerous (benign) tumors of nerves and skin (neurofibromas) and areas of abnormally decreased or increased coloration (hypo- or hyperpigmentation) of the skin. Areas of abnormal pigmentation typically include pale tan or light brown discolorations (cafe-au-lait spots) on the skin of the trunk and other regions as well as freckling, particularly under the arms (axillary) and in the groin (inguinal) area. 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 (plexiform neurofibromas). Individuals with NF1 may also develop benign tumor-like nodules of the colored regions of the eyes (Lisch nodules) or tumors of the optic nerves (second cranial nerves), which transmit nerve impulses from the innermost, nerve-rich membrane of the eyes (retinas) to the brain. More rarely, affected individuals may develop certain malignant (cancerous) tumors.
NF1 may also be characterized by unusual largeness of the head (macrocephaly) and relatively short stature. Additional abnormalities may also be present, such as episodes of uncontrolled electrical activity in the brain (seizures); learning disabilities; speech difficulties; abnormally increased activity (hyperactivity); and skeletal malformations, including progressive curvature of the spine (scoliosis), bowing of the lower legs, and improper development of certain bones. In individuals with NF1, associated symptoms and findings may vary greatly in range and severity from case to case. Most people with NF1 have normal intelligence but learning disabilities appear in about 50% of children with NF1.
NF1 is caused by changes (mutations) of a relatively large gene on the long arm (q) of chromosome 17 (17q11.2). The 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. In others with the disorder, NF1 is inherited as an autosomal dominant trait.
The name "neurofibromatosis" is sometimes used generally to describe NF1 as well as a second, distinct form of NF known as neurofibromatosis Type II (NF2). Also an autosomal dominant disorder, NF2 is primarily characterized by benign tumors of both acoustic nerves, leading to progressive hearing loss. The auditory nerves (eight cranial nerves) transmit nerve impulses from the inner ear to the brain.
The symptoms of neurofibromatosis type 1 usually appear during childhood. The disorder is progressive and, in some cases, the symptoms become more pronounced during puberty, pregnancy, or when hormonal changes take place. The range and severity of symptoms varies greatly among affected individuals and the rate of progression of this disorder is not predictable.
The first sign of neurofibromatosis type 1 is usually the appearance of multiple brown spots on the skin (cafe-au-lait) and freckling under the arms (axillary) or in the groin area (inguinal). According to the NIH Consensus Conference in 1987, a diagnosis of NF1 requires that there must be six such spots (5 mm in size) before puberty; these spots enlarge to 15mm after puberty. Small clumps of pigment develop on the iris of the eyes (Lisch nodules). The presence of Lisch nodules is highly indicative of NF1 as they occur in 97 percent of affected individuals. Freckling under the arm or in the area of the groin, along with Lisch nodules, are important criteria for the diagnosis of neurofibromatosis type 1.
Multiple tumors (neurofibromas) occur in neurofibromatosis type 1, forming on the nerves on or under the skin or in deeper areas of the body. Pain may or may not occur. Tumors can cause disfigurement and wrap around or penetrate the nerves. Orthopedic problems may develop including curvature of the spine (scoliosis) and a condition called pseudoarthrosis. This condition is characterized by loss of bone tissue (deossification) on weight-bearing long bones, followed by a fracture; the fracture does not form the normal mass of tissues (callus) that usually forms at a fracture site. This is commonly referred to as a "false joint." With pseudoarthrosis the long bones of the legs, especially the tibia, may become thin and bent (bowed), and may fracture easily. These breaks may fail to heal properly. Tumors may also develop on the nerves of the eye (optic gliomas). In a small number of affected individuals, certain types of malignant tumors may develop, especially malignant peripheral nerve sheath tumors.
Sexual development may be delayed or may occur early (precocious puberty) in individuals with neurofibromatosis type 1. In addition, about 50 percent of individuals with NF1 experience learning disabilities. (For more information on this disorder, choose "precocious puberty" as your search term in the Rare Disease Database.)
In the localized form of neurofibromatosis type 1, known as segmental neurofibromatosis, tumors are typically limited to one area of the body.
In about 50 percent of individuals with NF1, the disorder is inherited from a parent as an autosomal dominant trait. Sporadic or random mutations in the gene responsible for NF1, account for the remaining 50% of cases. The NF1 gene, a remarkably large gene, has been mapped to chromosome 17q11.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 17q11.2" refers to band 11.2 on the long arm of chromosome 17. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
According to investigators, the large size of the NF1 gene is consistent with the large percentage of cases resulting from spontaneous (sporadic) changes of the gene. The NF1 gene regulates (encodes for) the production of neurofibromin, a protein that functions as a tumor suppressor. Several different mutations of the NF1 gene have been identified in individuals with the disorder (e.g., 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 localized form of neurofibromatosis type 1 (segmental NF) appears to be caused by a genetic change that is not inherited in the same manner (somatic mutation) as the NF1 gene. The risk for recurrence in the children of people with this form of the disease has not been determined.
Neurofibromatosis type 1 is a rare disorder that affects males and females in equal numbers. All races and ethnic groups can be affected by this disorder. Neurofibromatosis type 1 is estimated to occur in 1 in 4,000 births. The diagnosis of neurofibromatosis type 1 is usually made during the first decade of life, based on characteristic skin freckling, cafe-au-lait spots, optic glioma, and/or pseudoarthrosis.
Symptoms of the following disorders may be similar to those of neurofibromatosis type 1. Comparisons may be useful for a differential diagnosis:
Neurofibromatosis type 2 (NF2) is a rare disorder that is genetically distinct from neurofibromatosis type 1 (NF1). NF2 is characterized by benign tumors on both auditory nerves (acoustic neuromas) and in other areas of the body. Other tumors of the central nervous system may develop including neurofibromas, meningiomas, gliomas, and/or schwannomas. Individuals with neurofibromatosis type 2 usually have fewer cafe-au-lait spots and skin neurofibromas than those with neurofibromatosis type 1. Other symptoms may include balance problems, buzzing or ringing in the ears (tinnitus), progressive hearing loss, facial spasms, and/or muscle weakness. (For more information on this disorder, choose "neurofibromatosis type 2" as your search term in the Rare Disease Database.)
McCune-Albright syndrome is a multisystem disorder characterized by abnormal fibrous tissue development (dysplasia) in one or more bones. Any bone of the body may be affected. Symptoms include increasing pain, bone fractures, and limited mobility. Shortening of the limbs and other skeletal deformities may occur. Abnormally early puberty and brown (cafe-au-lait) spots on the skin are also characteristic of this disease. Other symptoms may include an overactive thyroid gland (hyperthyroidism), other endocrine abnormalities, and a variety of bone and soft tissue tumors. (For more information on this disorder, choose "McCune-Albright" as your search term in the Rare Disease Database.)
Proteus syndrome is a rare genetic disorder characterized by abnormal and unequal (asymmetric) growth in any system of the body. Abnormalities of the skin, face, eyes, ears, lungs, skeletal muscles, and nerves occur, usually because one side of the body grows faster than the other. The symptoms of this disorder become apparent during the first year of life and may include skin lesions resembling birthmarks (nevi) and other soft tissue tumors (i.e., hemangiomas, lipomas, and lymphangiomas). Other symptoms may include mental impairment, seizures, visual abnormalities, and cysts in the lungs. (For more information on this disorder, choose "Proteus" as your search term in the Rare Disease Database.)
Tuberous sclerosis is a rare inherited neurological disorder characterized by seizures; mental retardation; developmental delays; lesions of the eyes and skin; and brain tumors. The first symptoms of tuberous sclerosis usually occur during infancy or early childhood. Approximately 60 to 90 percent of infants with tuberous sclerosis have brown (cafe-au-lait) or white (hypomelanotic) spots on the skin at birth. About 80 percent of affected children have seizures that may be accompanied by muscle spasms (myoclonic jerks) as their first symptoms. Benign tumors (fibromas) may present around or under the nails (periungual or subungual). (For more information on this disorder, choose "tuberous sclerosis" as your search term in the Rare Disease Database.)
Noonan syndrome is a rare genetic disorder characterized by distinctive malformations of the head and facial (craniofacial) area such as widely spaced eyes (ocular hypertelorism), drooping of the upper eyelids (ptosis), and prominent, low-set ears; webbing of the neck (pterygium colli); short stature; characteristic abnormalities of the breastbone (sternum); failure of one or both testes to descend into the scrotum (cryptorchidism) in affected males; and/or congenital heart defects (e.g., pulmonary stenosis, atrial septal defects). Some affected individuals may also have additional abnormalities including improper development of certain blood or lymph vessels, blood clotting and platelet deficiencies, and/or mild mental retardation. In rare cases, individuals with Noonan syndrome may also have pigmented birthmarks (nevi), small black or dark brown "freckle-like" spots (lentigines), and/or larger, light brown (café-au-lait) spots on the skin. Noonan syndrome may be inherited as an autosomal dominant trait. Cases in which a positive family history has not been found are thought to represent new genetic changes (mutations) that occur randomly, with no apparent cause (sporadic). (For more information on this disorder, choose "Noonan" as your search term in the Rare Disease Database.)
Neurofibromatosis-Noonan syndrome is characterized by the occurrence of neurofibromatosis type 1 in association with manifestations of Noonan syndrome. Associated symptoms and findings may include multiple benign tumors of the nerves and skin, short stature, webbing of the neck (pterygium colli), muscle weakness, and/or learning disabilities. Affected individuals may also have certain craniofacial abnormalities associated with Noonan syndrome including drooping of the upper eyelids (ptosis), low-set ears, and/or unusually prominent folds between the nose and the lips (nasolabial folds). In addition, congenital heart defects often seen in Noonan syndrome may be present, such as obstruction of the normal outflow of blood from the lower right chamber (ventricle) of the heart to the lungs (pulmonary stenosis) and/or an abnormal opening in the fibrous partition (septum) between the upper chambers (atria) of the heart (atrial septal defect). According to the medical literature, it is unclear whether Neurofibromatosis-Noonan syndrome is a rare variant of neurofibromatosis type 1, is due to the chance occurrence of both disorders in the same individuals, represents a rare variant of Noonan syndrome, or represents a new disease entity.
Watson syndrome is an extremely rare inherited disorder characterized by the appearance of light brown (café-au-lait) spots and freckling on the skin; short stature; obstruction of the normal outflow of blood from the lower right chamber (ventricle) of the heart to the lungs (pulmonary stenosis); and diminished intellectual capabilities. In some cases, affected individuals may also have additional abnormalities including an unusually large head (macrocephaly); limited movements of the ankles and knees; the formation of soft, fibrous, benign tumors (neurofibromata) in certain areas of the body; and/or, in rare cases, the appearance of benign tumor-like nodules on the colored portion of the eyes (iris lisch nodules). In the past, Watson syndrome was sometimes confused with neurofibromatosis type 1. Watson syndrome is due to a genetic mutation in the NF-1 gene located on the long arm of chromosome 17 (17q11.2). Watson syndrome is inherited as an autosomal dominant genetic trait.
Neurofibromatosis type 1 (NF1) is diagnosed if two or more of the following are present:
Six or more cafe-au-lait spots;
Two or more neurofibromas of any type or 1 "plexiform" neurofibroma;
Freckling under the arms (axillary) or in the groin area (inguinal);
Benign tumor of the optic nerve (glioma);
Two or more Lisch nodules in the iris of the eyes;
Lesions in the bone (sphenoid dysplasia or thinning of long bones) with or without pseudoarthrosis;
A parent, sibling, or child with neurofibromatosis Type 1.
People with neurofibromatosis type 1 may undergo surgery to remove particularly troublesome tumors. 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.
Genetic counseling will be of benefit for people with neurofibromatosis type 1 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
For information about clinical trials sponsored by private sources, contact:
The Children's Tumor Foundation launched an 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.
A Phase I/II trial of PEG12000 Interferon alfa-2b (PEG-Intron) is in progress at several locations. This study is designed to determine the maximum-tolerated dose, toxicity profile, and efficacy of PEG-Intron in NF1 patients with progressively disfiguring or disabling plexiform neurofibromas. For more information on this study, sponsored by Schering-Plough, contact:
Beverly Brannon, Study Coordinator
Phone: (412) 692-7070
Several NIH studies focusing on children and young adults with NF1 are presently (2004) in progress. The purpose of these studies is to measure the success and safety of the drug Pirfenidone in slowing the growth of, or possibly shrinking, plexiform neurofibromas. For information on these studies, contact the government sources listed at the beginning of this section.
The National Cancer Institute is sponsoring a study of the use of the investigational drug R115777 to treat children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas. This study will examine whether the drug can shrink or slow the growth of plexiform neurofibromas, and determine the side effects related to treatment. Patients with NF1 between three and 25 years of age may be eligible for this study. This trial is being conducted at multiple institutions. For more information, contact;
Andrea Gillespie, Study Coordinator
Phone: (301) 402-1848
Researchers at the University of Cincinnati are studying tumor growth factors, growth factor receptors, and signaling pathways in neurofibroma cells in individuals with neurofibromatosis type 1. They require neurofibroma tissue from NF1 patients. For more information, contact:
Dr. Nancy Ratner
Phone: (513) 558-6079
Fax: (513) 558-4454
A co-founder of the National Neurofibromatosis Foundation, Allan Rubenstein, MD, has founded a drug development company, NexGenix Pharmaceuticals, focused on fighting NF1 and NF2. Information on studies of drug treatments for neurofibromatosis is available at:
Short MP. Neurofibromatosis Type 1. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:563-64.
Beers MH, Berkow R., eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:.
Berkow R., ed. The Merck Manual-Home Edition.2nd ed. Whitehouse Station, NJ: Merck Research Laboratories; 2003:.
Larson DE. ed. Mayo Clinic Family Health Book. New York, NY: William Morrow and Company, Inc; 1996:.
Bennett JC, Plum F. Eds. Cecil Textbook of Medicine. 20th ed. W.B. Saunders Co., Philadelphia, PA; 1996.
Stephens K. Genetics of neurofibromatosis 1-associated peripheral nerve sheath tumors. Cancer Invest. 2003;21:897-914.
Conti P, Pansini G, Mouchaty H, et al. Spinal neurinomas: retrospective analysis and long-term outcome of 179 consecutively operated cases and review of the literature. Surg Neurol. 2004;61:34-43; discussion 44.
Young TL. Ophthalmic genetics/inherited eye disease. Curr Opin Ophthalmol. 2003;14:296-303.
Bryant J, Farmer J, Kessler LJ, et al. Pheochromocytoma: the expanding genetic differential diagnosis. J Natl Cancer Inst. 2003;20:1196-204.
Joyhnson MV. Brain plasticity in paediatric neurology. Eur J Paediatr Neurol. 2003;7:105-13.
Tamer E, Yalcin B, Alli N. Multiple nodular plexiform neurofibromas in a neurofibromatosis 1 family: a familial tendency? A case report and review of the literature. Int J Dermatol. 2003;42:357-58.
Reynolds RM, Browning GG, Nawroz I, et al. Von Recklinghausen's neurofibromatosis: neurofibromatosis type 1. Lancet. 2003;361:1552-54.
McLaughlin ME, Jacks T. Neurofibromatosis type 1. Methods Mol Biol. 2003;222:223-37.
Kandt RS. Tuberous sclerosis complex and neurofibromatosis type 1: the two most common neurocutaneous diseases. Neurol Clin. 2002;20:941-64.
Abdel-Wanis ME, Kawahara N. Bone development in neurofibromatosis 1. Med Hypotheses. 2003;60:459-62.
Rosser TL, Packer RJ. Neurocognitive dysfunction in children with neurofibromatosis type 1. Curr Neurol Neurosci Rep. 2003;3:129-36.
Ferner RE, O'Doherty MJ. Neurofibroma and schwannoma. Curr Opin Neurol. 2002;15:679-84.
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Children's Tumor Foundation
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March of Dimes Birth Defects Foundation
1275 Mamaroneck Avenue
White Plains, NY 10605
213 S. Wheaton Ave.
Wheaton, IL 60187
Neurofibromatosis Clinic at Texas Children's Hospital
6701 Fannin Street, #1560
Houston, TX 77030
Cedars-Sinai Medical Genetics Institute
8700 Beverly Blvd
PACT Suite 400
Los Angeles, CA 90048
The Children's Hospital of Philadelphia
34th Street and Civic Center Boulevard
Philadelphia, PA 19104
Internet: http://www.chop.edu/healthinfo/fibromatosis-and-desmoid-tumors.html or http://www.chop.edu/service/neurofibromatosis/home.html
Children's National Medical Center
Attn: Kenneth Rosenbaum MD
111 Michigan Ave. NW
Washington, DC 20010
NIH/National Institute of Neurological Disorders and Stroke
P.O. Box 5801
Bethesda, MD 20824
Massachusetts General Hospital Neurofibromatosis Clinic
15 Parkman St. 8th Floor, Room 835
Boston, MA 02114
New England Consortium of Metabolic Programs
Children's Hospital Boston
1 Autumn Street, Room 525
Boston, MA 02115
Comer Children's Hospital - University of Chicago (Neurofibromatosis Clinic)
5721 S. Maryland Avenue, MC3055
Chicago, IL 60637
BC Neurofibromatosis Foundation
Victoria, BC, V8R 6S4
Tel: 800385BCNF (2263)
Rare Cancer Alliance
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Green Valley, AZ 85614
Genetic and Rare Diseases (GARD) Information Center
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PO Box 241956
Los Angeles, CA 90024
Let Them Hear Foundation
1900 University Avenue, Suite 101
East Palo Alto, CA 94303
Alberta Neurofibromatosis Association
636 Hunterfield Place NW
Alberta, T2K 4L6
Email: email@example.com or firstname.lastname@example.org
American Society of Clinical Oncology
2318 Mill Road Suite 800
Alexandria, VA 22314
Medical Home Portal
Dept. of Pediatrics
University of Utah
P.O. Box 581289
Salt Lake City, UT 84158
RASopathies Network USA
244 Taos Road
Altadena, CA 91001-3953
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