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.
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:
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