Neurofibromatosis are hereditary diseases characterized by the formation of benign tumors in the skin, soft tissues, nervous system and internal organs. There are 6 types of neurofibromatosis, types I and II are clinically significant. Common symptoms include neurofibromas on the skin, tumors of the spinal roots, auditory and optic nerves, pigmented spots, bone deformities. Diagnosis is based on the data of examination of patients, detection of tumors using MRI and CT of the spinal cord and brain, internal organs. Treatment is symptomatic – tumor resection, X-ray therapy, and chemotherapy are performed.
Q85.0 Neurofibromatosis (non-malignant)
Neurofibromas are benign tumors that develop from the membranes of nerve fibers. Most often they are located in the layers of the skin and subcutaneous tissue, sometimes they affect the brain, nerve fibers, spinal cord roots, soft tissues, internal organs. Neurofibromatosis is a disease in which numerous neurofibromas are formed. The prevalence of different types of pathology varies significantly: the incidence of type 1 is 1:2,500, type 2 is 1:50,000. Other variants are even rarer, their exact epidemiology has not been determined. Gender and racial predisposition were not revealed. The debut of clinical manifestations is possible at any age, depending on the type of disease.
The formation of multiple neurofibromas is determined genetically. In neurofibromatosis I, there is a mutation of the NF1 gene located on the long arm of chromosome 17. It belongs to the tumor tissue growth suppressor genes, most of which are of neuroectodermal origin. With a defect in the NF1 gene, the synthesis of proteins responsible for cell proliferation is disrupted. Mutations are in the nature of translocations, deletions, inversions, point changes. More than 80% of them lead to the synthesis of non-functional proteins or to the complete absence of protein molecules. Inheritance occurs by an autosomal dominant mechanism with a high degree of penetration: in the presence of a mutated gene in one of the parents, the probability of a child’s disease is 50%, if both parents have a mutation, the risk increases to 80-90%. There are cases of spontaneous mutations.
The cause of neurofibromatosis II is a mutational change in the NF2 gene localized on chromosome 22. It encodes the production of merlin protein (schwannomine)– a tumor suppressor. The type of inheritance is autosomal dominant with a small degree of penetration. The transmission of one mutant gene often does not manifest itself, since the second gene ensures the synthesis of a sufficient number of proteins. If it is damaged, the synthesis of normal merlin fractions stops, cell proliferation increases, and neoplasm develops. In other types of neurofibromatosis, there are also mutations in the genes that ensure the reproduction of tumor growth suppressor protein molecules.
A common pathogenetic mechanism for the development of neurofibromatosis is a hereditary deficiency of a protein that suppresses the processes of tumor cell proliferation in tissues of neuroectodermal origin. With a mutation of one gene, the production of tumor suppressors stops by half, the balance of cell growth and death shifts towards mitotic division. A normal allelic gene partially compensates for protein deficiency. The severity of neurofibromatosis is determined by how much the defective gene affects the activity of the suppressor protein – partially or completely disrupts functionality, completely blocks production. In addition, the severity of clinical signs depends on the preservation of antitumor immunity.
Benign tumor formations consisting of connective tissue and pigment cells are formed in many organs and tissues of patients. Neurinomas form on the nerve trunks; pigmented areas, fatty plaques, dilated vessels form on the skin surface; phacomatosis forms on the retina. The structure of the bones changes, they remain underdeveloped or excessively thicken, the vertebral column bends.
Diseases are manifested by signs of damage to the skin, nervous system. The classic clinical variant is neurofibromatosis type I, which accounts for 90% of cases of the disease. A characteristic symptom is hyperpigmentation. Patients at birth or in early childhood have skin spots, the color of which varies from light golden to brown “coffee with milk”. In some cases, the spots have a purple or blue tint. Lish nodules (spots of pigment – hamartomas) of small size, whitish or light beige, visible only during ophthalmological examination, are found on the iris of the eye. They are a specific sign of neurofibromatosis 1, formed as they grow older: in children under 4 years of age, the prevalence is 22%, from 5 to 9 years – 41%, from 10 to 19 years – 85%, after 20 years – 95%.
During puberty and later, cutaneous and plexiform neurofibromas are formed, located respectively subcutaneously (on small nerve fibers innervating the skin) and on large nerves. They are small benign neoplasms. Cutaneous neurofibromas are perceived as a cosmetic defect, at a certain location they are injured. Plexiform tumors localized along the peripheral nerves are detected on the conjunctiva, eyelids, abdominal cavity and mediastinum. They are manifested by chronic pain, numbness, convulsions, paralysis. CNS tumors are located inside the skull, represented by optic nerve fiber gliomas, astrocytomas, ependymomas, auditory nerve neurinomas, meningiomas and neurofibromas. The clinical picture is determined by the size of neoplasms, the involvement of brain structures in the pathological process. Mental development disorders are diagnosed in childhood: cognitive decline, hyperactivity, rarely – dementia.
In severe neurofibromatosis, the bone system is deformed. Patients develop scoliosis, marginal structural changes in the vertebral bodies and their processes, erosive lesions of the edges of the intervertebral openings and posterior ribs. Characterized by atrophy or, conversely, hypertrophy of tubular bones. Bones are often curved, periosteal ridges and layers are found on the surface. Neurofibromas can form in the cavities of bones. If the bones of the skull are involved in the process, an external asymmetry appears, most pronounced when the facial part and eye sockets are affected. The arch of the skull may have atrophied areas, defects, usures, sometimes there is a local increase in bone matter.
In type 2, highly differentiated tumors are formed, which, however, are more aggressive than in type 1 disease. There are no pigment spots. Neurinomas are formed – mobile and painful neoplasia. Often they are localized on the auditory nerve, causing hearing loss. Neurofibromatosis type 3 is characterized by a large number of neurofibromas, accelerated development of neurolemmas and optic nerve gliomas, leading to visual impairment. A specific sign is the appearance of neurofibromas on the palms. With type 4 disease, the symptoms are similar, the risk of damage to the visual fibers remains. Type 5 is characterized by pigmented dark spots, large tumors that provoke asymmetry of the body. The course of type 6 is accompanied only by pigment spots. With type 7, medium-sized neurofibromas are detected, there is no hyperpigmentation.
In 10% of cases, neurofibromas transform into malignant tumors. Patients with long catamnestic experience, pregnant women are at high risk. 6% of children have impaired mental development: they have problems in mastering learning skills (reading, writing, counting), have difficulty remembering new information, adapt to unfamiliar situations for a long time. Patients of all ages are prone to depression because they experience discomfort, shame and awkwardness due to disfigured appearance. Multiple neurofibromas provoke endocrine disorders, epileptic seizures, muscle hypotension, renal and pulmonary artery stenosis, pulmonary cysts, interstitial pneumonia, clitoral hypertrophy, gastrointestinal disorders.
Suspicion of neurofibromatosis occurs with multiple subcutaneous tumors, age spots, spinal schwannoma, hearing and vision impairment. The examination is carried out by a dermatovenerologist, neurologist, ophthalmologist, otolaryngologist and geneticist. Before instrumental and laboratory procedures, a family and personal history is collected, a clinical survey and examination is carried out. In the course of genealogical analysis, the transmission of the disease in several generations is revealed, less often the primary spontaneous mutation is determined. Neurofibromas, pigmented areas (with certain types of disease), spinal curvature, bone deformities, visual, hearing, and movement coordination disorders are found on the body of patients. Differential diagnostics of various variants of neurofibromatosis is performed, Proteus syndrome, multiple lipomatosis, Klippel-Trenone-Weber syndrome are excluded. To clarify the diagnosis , the following are prescribed:
- MRI, CT. Imaging methods of research allow to determine the presence of neurofibromas in the brain, spine, internal organs. Bilateral neurinomas of 7 pairs of cranial nerves are a diagnostic criterion for type II neurofibromatosis. Gliomas, schwannomas, and meningiomas are often detected. Type I is characterized by the development of plexiform and common neoplasms, gliomas.
- Radiography of skeletal bones. The diagnostic procedure is performed to confirm and assess the severity of scoliosis, bone atrophy and hypertrophy, local thickening and erosive lesions of bone structures. In most types of the disease, thinning of the cortical layer, false joints, dysplasia of the wings of the sphenoid bone, arched curvature of the tibia and fibula, cysts of long bones are observed.
- Ophthalmological examination. Neurofibromatosis type 1 is accompanied by plexiform neurofibroma of the eyelids, melanocytic hamartomas of the iris, glioma of optical nerve fibers, astrocytic hamartoma of the retina, thickening of corneal nerves, conjunctival neurofibroma, ischemic lesions of the retinal venules. A pathognomonic sign is spots of a light shade on the fundus and iris (hamartomas). In type 2, posterior subcapsular cataract, clouding of the lens is diagnosed.
- Audiological research. With a tumor lesion of the auditory nerves and complaints of increasing deafness (hearing loss), electrocochleography and impedance measurement are performed. The results indicate a decrease in hearing acuity, the presence of auditory neuropathy, determine the cause and localization of the disorder.
Currently, the therapy of this group of diseases consists in symptomatic care for patients. Patients regularly undergo examinations aimed at controlling the formation and enlargement of tumors. In the presence of neurofibromas that provoke pain, located in places of increased risk of injury, squeezing or displacing vital organs, their surgical removal is performed. Classical methods of resection of neoplasias and nerve sections, cryodestruction, laser surgery are used. With multiple neoplasms, radiation therapy and chemotherapy are prescribed. Patients with damage to the musculoskeletal system are shown rehabilitation measures (physiotherapy, physical therapy).
Methods of etiological treatment of neurofibromatosis are being actively developed. Therapy with RAS (tumor growth activator proteins) inhibitors is at the stage of clinical trials in persons with neurofibromatosis of the first type. The methods of genetic engineering pass the stage of theoretical development. The efforts of genetic scientists are aimed at creating and introducing into the body of patients the normal NF1 gene responsible for the synthesis of neurofibromine, at decoding and introducing the FN2 gene that provides transcription of the schwannomine protein. In some medical centers, attempts are being made to use pathogenetic therapy, which is based on the complex use of mast cell membrane stabilizers, antiproliferative drugs and enzymes that correct metabolic processes.
Prognosis and prevention
Neurofibromatosis are prognostically favorable diseases – malignancy of tumors occurs rarely, in most cases patients remain able-bodied and socially adapted. With proper and regular rehabilitation measures, disorders of the bone system and mental retardation are successfully corrected. Since the disease is hereditary, prevention is possible at the stage of pregnancy planning, couples from risk groups (with a burdened family history) are recommended medical and genetic counseling to determine the probability of having a sick child.