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Additional entries in our database that you might find useful:   Neurofibromatosis type 1 (NF1)

What

Plexiform neurofibromas are a type of benign (i.e. nonmalignant, non-spreading) tumor seen in patients most of whom have neurofibromatosis type 1 (for specifics on NF1 please see separate entry). By definition, plexiform neurofibromas are tumors of the peripheral nerve sheath (the insulating material around nerves) that form along large nerve trunks, multiple small branches of nerves, or spinal roots (nerves that arise from the spinal cord) causing enlargement. This type of tumor is ultimately composed of the surrounded nerve sheaths, tumor cells, collagen, and may resemble a "bag of worms." In general, about 40% of plexiform lesions are large and 65% asymptomatic. It is a slow growing tumor and its growth pattern and growth rate are unpredictable. Plexiform lesions can be limited to deep soft-tissue, or they may affect the skin and superficial muscle. Tumors in skin or underlying muscle may yield a change in appearance such as a noticeable increase in size or deformation of nearby tissue. Plexiform neurofibromas can also displace or penetrate neighboring organs or invade into bone. This type of tumor can impair proper function, cause pain, result in disfigurement, and can become malignant. Plexiform Neurofibroma tumors occur in several common sites. The most common sites in the chest are paraspinal (next to the spine; these tumors can cause systemic elevated blood pressure), in the anterior mediastinum (the area behind the “breast bone” or sternum) and in the supraclavicular region (above the “collar bone”). The most common sites in the pelvis and abdomen are paraspinal, around the sciatic nerve (a nerve that extends from the pelvis to the thigh), and in the perirectal (next to the rectum) fat and muscle.

Who

Neurofibromatosis type 1 occurs in approximately 1:3000 live births. Plexiform neurofibromas are a common complication of NF-1, yet the frequency among pediatric patients seems to increase as the children near adolescence. A recent study of adults (patients 16 years and older) determined that 35% of the NF-1 patients had plexiform neurofibromas in the abdomen and pelvis. 4% had plexiform neurofibromas in the supraclavicular region and chest. Another 32% had superficial plexiform tumors of the skin. Of all those studied as many as 71% had plexiform neurofibromas. The age of a child generally correlates with the location of developing plexiform neurofibromas. Diffuse plexiform neurofibromas of the head and neck usually develop before one year of age, and diffuse plexiform neurofibromas of other parts of the body usually appear before adolescence. Deep nodular plexiform neurofibromas, however, are infrequently observed in early childhood and may remain asymptomatic even in adulthood. malignant peripheral nerve sheath tumors (plexiform neurofibromas that do not remain benign) are the most frequent malignant NF1 associated tumors, and occur in 10% of patients.

Signs and Symptoms

The main signs of Plexiform Neurofibroma tumors are pain, loss of function and cosmetic deformity. Another symptom is Hyperpigmentation Overlying a Plexiform Neurofibroma (HOPN). HOPN refers to a color change that may occur in the skin covering the tumor. Affected skin may appear orange, grow more hair than usual, develop an uneven surface (parts may be raised) or lack distinct borders.

Possible Causes

NF1 is one of the most common dominantly inherited genetic disorders in the human population. A mutation (mistake) in the NF1 gene, a piece of DNA that carries the instructions for a protein called neurofibrin, causes neurofibrin to be manufactured incorrectly or not at all. Neurofibrin is thought to help monitor the activity of another protein, ras, which is in charge of regulating cell growth. Too little neurofibrin may lead to uncontrolled cell growth and tumor formation. Those with NF1 are at 1,000 to 100,000 times the risk of the general population to develop a neurofibrosarcoma. Half of the children with NF1 inherited the disorder from one of their parents. A dominant genetic disorder is one that requires only one defective gene (out of the two inherited -- one from mom, and one from dad) to produce symptoms. Mendelian genetics predict that children of a parent with NF1 (assuming that the other parent does not have the disorder) have a 50% chance of inheriting NF1. Not all parents who pass NF1 on to their children have symptoms themselves. NF1 can arise first in the parents of affected children via a type of inheritance called gonadal (sex cell) mosaicism. Gonadal mosaicism occurs when a mutation only arises in a developing fetus' sperm or egg cells. Adult males and females with this condition may not show any signs of a genetic disease, yet their children (a product of those sperm and egg cells) have the risk of inheriting the mutation. The other half of children with NF1 acquired a new mutation in early fetal development. The spontaneous mutation rate for the NF1 gene is among the highest known for any gene in humans. When this novel mutation occurs after fertilization, the genetic abnormality no longer affects all of the cells. The signs and symptoms associated with NF1 are proportional to the amount of cells affected by the embryonic mutation and how early the mutation occurred in fetal development. Early DNA mutations cause systemic symptoms, clinically identical to the non-mosaic forms mentioned above. Later DNA mutations yield localized disease, often called segmental. This is most likely the case when a child without the classical clinical features of neurofibromatosis type I develops a plexiform neurofibroma. Segmental manifestations may affect a small area, a limb, a quadrant and occasionally one half of the body. The growth of these tumors is unpredictable and the factors that influence their growth are largely unknown, although there appears to be an increase in growth rate approaching puberty.

Diagnosis

The diagnosis of NF1 is based on clinical findings. Please see the separate entry for NF1 for complete requirements. As mentioned above, not all children with a plexiform neurofibroma necessarily carry the clinical findings of NF1. Plexiform neurofibroma tumors can be diagnosed with biopsy and imaging studies. Children with NF1 need to be seen regularly by their pediatrician for check-ups. Doctors should monitor young adults carefully for signs of malignant transformation and order biopsy tests for any neurofibromas that grow rapidly. Imaging should be considered in any symptomatic individuals.

Treatment

Despite being one of the most common features of NF1, plexiform neurofibroma treatment has been limited by a scientific understanding of the biologic basis of these tumors. Until recently, options have been limited, with the only truly effective treatment being complete surgical removal. Although characteristically benign, these tumors may cause pain, disfigurement, functional changes, and may become malignant. Surgery, however, is often not a cure because the invasive nature, number and location of the tumors prevent complete resection. These tumors tend to grow back at the site of removal. Resection of benign neurofibroma plexiform tumors should be considered with great caution because of the significant chance of producing injury. Also, the lifetime risk of malignancy within the tumor is probably less than 10%. Alternatives to surgery for the treatment of plexiform neurofibroma tumors are showing promise. A recent clinical trial using retinoic acid in children with progressive tumors showed that tumor size in 86% of patients remained stable after 18 months of beginning the drug. Another study of an antiangiogenesis drug (interferon-α ) reports that 96% of patients’ previously progressing tumors remained stable 18 months after starting the medication. A pilot study using thalidomide (as an angiogenesis inhibitor) for treatment was recently completed (Gupta, 2003). In this trial, 20 patients more than 5 years of age were treated. The medication was well tolerated at lower doses and some of the patients showed a reduction in tumor size. Currently, trials for oral farnesyl protein transferase inhibitors and cytokine modulators are being conducted. One of the difficulties in evaluating the success of any drug is the fact that the tumor may go through cycles where it grows and then remains dormant. This dormant period may last months to years making evaluation of new therapies rather difficult unless the tumor actually decreases in size.

Prognosis

Plexiform neurofibromas can cause significant health problems and can be fatal if the tumor becomes malignant. Such a malignancy arising from a plexiform tumor occurs in about 3-5% of those with NF-1. Most of these tumor transformations occur in young males at or about the age of 10 years. Only 16% of the youth with the malignant peripheral nerve tumors live beyond 5 years of diagnosis. This poor survival rate is likely due to late detection. Much research is dedicated to identification of those who may be at high risk for benign-malignant tumor transformation, so that their tumors can be treated earlier and their chances for survival better. Additional research into pharmaceutical alternatives should bring improved survival and better quality of life to children and families with plexiform neurofibromas

Connect with other parents

In the spirit of community and support, Madisons Foundation offers the unique service of connecting parents of children with rare diseases. If you would like to be connected to other parents of children with this disease, please fill out this brief form.

Weblinks

Clinical Trials.gov
A great website with links to ongoing clinical trials.

Gene Tests
A very thorough, somewhat complex site describing NF1 and plexiform neurofibroma tumors. It is somewhat technical but with good definitions of many medical terms. Search for NF1 under GeneReviews.

Google Search for Neurofibroma Plexiform Tumors

References and Sources

Gupta A, Cohen BH, Ruggieri P, Packer RJ, Phillips PC. Phase I study of thalidomide for the treatment of plexiform neurofibroma in neurofibromatosis 1. Neurology. 2003 Jan 14;60(1):130-2. PMID: 12525736 [PubMed - indexed for MEDLINE Neville HL, Seymour-Dempsey K, Slopis J, Gill BS, Moore BD, Lally KP, Andrassy RJ (2001) The role of surgery in children with neurofibromatosis. J Pediatr Surg 36:25-9. Packer RJ, Rosser T (2002) Therapy for Plexiform Neurofibromas in Children with Neurofibromatosis 1: An Overview. J. Child Neurology 17(8):638-41. Riccardi VM, Eichner JE. Neurofibromatosis: phenotype, natural history, and pathogenesis. Baltimore: Johns Hopkins University Press, 1994:46 Tinschert S, Naumann I, Stegmann E, Buske A, Kaufmann D, Thiel G, Jenne DE. Segmental neurofibromatosis is caused by somatic mutation of the neurofibromatosis type 1 (NF1) gene. Eur J Hum Genet. 2000 Jun;8(6):455-9. Tonsgard JH, Kwak SM, Short MP, Dachman AH (1998) CT imaging in adults with neurofibromatosis-1: frequent asymptomatic plexiform lesions. Neurology 50:1755-60 Zoller M, Rembeck B, Akesson HO, Angervall L (1995) Life expectancy, mortality and prognostic factors in neurofibromatosis type 1. A twelve-year follow-up of an epidemiological study in Goteborg, Sweden. Acta Derm Venereol 75:136-40