Neurofibromatosis type I

Neurofibromatosis type 1 (short: NF1), also disease Recklinghausen (named after its discoverer, Friedrich Daniel von Recklinghausen) or peripheral neurofibromatosis, is an autosomal dominant and monogenic inherited multisystem disease that primarily affects the skin and nervous system. It is therefore associated with the neurocutaneous disorders ( phakomatoses ).

Typical changes on the skin are multiple café-au -lait spots and neurofibromas. In the central nervous system (CNS) occur more frequently tumors of different localization. Patients may be less talented and suffer from epileptic seizures. Furthermore, regularly also affected eyes and bones.

As a café -au -lait spots are called cafe au lait -colored hyperpigmentation of the skin. They are in the level of the skin, may occur and are harmless in all people. In people with NF1 they occur frequently. As a neurofibroma is called benign tumors, which originate from the cells of Schwann sheaths, less running in the skin nerve fibers.

Neurofibromatosis is caused by a mutation in a gene which is normally inhibitory influences the cell proliferation. It therefore comes to an excessive tissue proliferation and thereby to the typical changes. The diagnosis is usually made in childhood on the basis of the clinical picture. Since it is a genetic disease in Recklinghausen 's disease, is a therapy which eliminates its cause, is not currently possible. There are therefore only changes treated that are disruptive or dangerous to the patient. Another well-known form of neurofibromatosis is the neurofibromatosis type 2 ( NF2).

• 5.1 skin
• 5.2 Nervous System
• 5.3 eye
• 5.4 bone

History

A rather anecdotal first description can be found in Robert William Smith, 1849. Friedrich Daniel von Recklinghausen in 1882 laid the first precise clinical and pathological characterization ago. Alex Thomsen gave out in 1900 for the first statistical data, and a detailed bibliography. Joseph Merrick, the so-called " Elephant Man ", was long regarded as an example of the distorting effects of Recklinghausen 's disease. His life in Victorian England was the basis for books and movies, particularly David Lynch's The Elephant Man. Merricks severe distortions characterized the widespread misconceptions of the monstrosity of patients with neurofibromatosis type 1 by a DNA analysis in 2003 Merrick suffered from Proteus syndrome but on, with an additional disease in neurofibromatosis type 1 is likely. The oldest surviving written descriptions of the disease date from the 13th century.

Incidence, inheritance and epidemiology

It is estimated about 30 to 40 sufferers per 100,000 inhabitants, which corresponds to an expectation of an affected child per 2500-3300 births. In half of the cases, it is assumed that a new mutation leads to the changes in the genome. All previous observations confirm an autosomal dominant trait, which means that a concerned parent with a probability of 50 percent ( or, depending on genotype also 100 percent) passes on the disease to his children. One finds no different frequencies in different regions of the world or members of other ethnic groups. However Men are affected slightly more often than women. The high rate of new mutation is explained by the fact that the NF -1 gene is very large and offers plenty of surface for genetic changes.

Pathogenesis and molecular biology

Neurofibromatosis type 1 was one of the first hereditary tumor diseases, the genetics could be determined. The neurofibromatosis type 1 locus is located on chromosome 17 q11.2 locus. It is complex and encodes for a might the intracellular signaling pathway modulating protein. The neurofibromatosis type 1 gene locus spans approximately 400,000 base pairs. In a more than 40,000 base pair intron of this locus, there are three genes in the opposite direction of reading: OMPG encodes a membrane-bound glycoprotein of oligodendrocyte myelin EVI2A and EVI2B encode viral insertion sequences. At the neurofibromatosis type 1 locus translocations (1.17 ) and ( 17.22 ), deletions, insertions and point mutations have been described. The 50 exons of the gene encoding large transcripts for various approx 9 to 11 kB. An approximately 7800 base pairs of comprehensive open reading frame of the genomic locus allows the derivation of a protein with 2500 amino acids. The neurofibromatosis type -1 peptide ( neurofibromin ) shows sequence homologies with known mammalian GAP ( GTPase activating protein) and the IRA1 and Ira2 genes of yeast. The GAP - related domain of the NF- 1 peptide binds in vitro to the " ras p21 " protein. The catalytic domain of NF- 1 stimulates GTPase activity of Ras p21. If GTPases are activated by their (individual ) CAP, then hydrolyze the bound GTP to GDP and as such are no longer able to stimulate their effector. This effector is in the case of ras p21 a mediated via the phosphatidylinositol pathway mitogenic ( cell division stimulant ) signal. Defects GAPs can thus no longer a mitogenic signal off, the cells proliferate uncontrollably.

Pathology

Tumors

In neurofibromatosis come a number of tumors, both the central nervous system affecting as can also occur outside of it, heaped before.

Tumors of the nervous system

Neurofibromas

For the disease especially characteristic is the occurrence of neurofibromas, which are in contrast to sporadic neurofibromas occurring frequently is neurofibromas of the skin ( dermal neurofibromas ) or so-called plexiform neurofibromas. Dermal neurofibromas are benign, well-defined, located under the skin, small skin nerve branches outgoing tumors that consist of Schwann cells and fibroblast-like cells. Plexiform neurofibromas infiltrate diffusely larger nerve branches and thus lead to a piston-shaped swelling. Unlike ordinary neurofibromas the risk of malignant degeneration with about ten percent is significantly increased.

Malignant peripheral nerve sheath tumors

Malignant peripheral nerve sheath tumors in neurofibromatosis occur beginning at a young age and can histologically to contain skeletal muscle reminiscent rhabdomyoblastische or glandular glandular elements. Such tumors are also referred to as the Triton 's tumor, are highly characteristic of the neurofibromatosis type 1

Gliomas

The majority of gliomas occurring in neurofibromatosis type 1 make in the area of the optic nerve ( optic nerve ) of localized benign pilocytic astrocytomas, which are referred to in this localization as Optikusgliome. In neurofibromatosis type 1 Optikusgliome occur characteristically bilaterally and so affect both optic nerves. Optikusgliome can with neurofibromatosis type 1 have a many years of static course in patients. Other gliomas, which occur frequently in neurofibromatosis type 1, diffuse astrocytomas and malignant glioblastoma.

Tumors outside the nervous system

The occurrence of pheochromocytomas, tumors of the adrenal medulla is increased. The same is true for other rare tumors such as rhabdomyosarcomas, the Juvenile xanthogranuloma, gastrointestinal stromal tumors ( GIST), medullary thyroid carcinomas, and Chronic myelomonocytic leukemia.

Pigmentary disorders

Café -au -lait spots, freckling in the field of both underarms ( axillary freckling so-called ) and Lisch nodules are due to changes in the melanocytes of the skin and are often the first manifestation of the disease. Histologically, the ratio of melanocytes to keratinocytes, which has already moved in Neuofibromatose type 1 in the non-affected skin, further increases in the range of café-au- lait spots and freckling. The Lisch nodules occurring in the region of the iris of the eye is characterized histologically by small pigmented hamartomas.

Changes in bone and blood vessels

The eye socket is often deformed by a dysplasia of the sphenoid wing in the Neuofibromatose type 1. Deformations of the vertebral bodies often lead to severe scoliosis. The long bones of the extremities may be deformed. In the area of the blood vessels can fibromuscular dysplasia occur which may in particular relate to the renal arteries.

Clinical manifestations

Skin

Café -au -lait spots and discoloration of the armpit are distinctive skin lesions. In more than 95 percent of the cases, café -au -lait spots found in patients with neurofibromatosis Recklinghausen. About 80 percent have more than six large hyperpigmented areas. However, café -au -lait spots also occur in about ten percent of the population not affected. It is in this change are large ( up to several centimeters ), sharp and irregular margins pale to dark brown spots. They are distributed on the body without apparent order. There is a proliferation of melanocytes.

The so-called freckling ( engl. = freckle freckles, pits, speckles ) is a freckle- like discoloration of the body that are normally not exposed to sunlight. Most notable of these changes are in the armpit and groin. Since the freckling in patients occurs in about 90 percent with neurofibromatosis type 1, it is a diagnostically groundbreaking appearance. In addition, diffuse color changes of the trunk ( lentiginosis ) are described, which also occur frequently in the axillae.

Neurofibromas are tumors of the peripheral nervous system, which is manifested primarily in the area of the skin. They typically occur cutaneously ( cutis = skin tissue ), subcutaneously ( subcutaneous = subcutaneous tissue) or plexiform neurofibromas as on. The skin of the patient may be covered with up to 10,000 tumors of various sizes. They vary in diameter from a few millimeters to several centimeters, depending on the lesion. The neurofibromas may be below the surface and then stand out as undulating surface texture of the skin. Others can hemispherical rest on or adhere to the skin in the form of a bag. It is striking that they yield when pressure in the depth of what is called a buttonhole phenomenon or doorbell phenomenon. With this simple experiment one can easily distinguish a neurofibroma from a lipoma. The tumors are usually skin colored, but may be reddish, bluish or purple appear. The cutaneous neurofibromas have a smooth, homogeneous consistency.

The deeper subcutaneous neurofibromas are rough thickening, extending from the peripheral nerves. Since the growths also press on the nerves themselves, they often lead to pain and altered sensation.

The plexiform tumors are not uncommon on the face, neck, located on the hip and lower leg. You can reach partially an enormous size and show the unusual palpation of multiple strand-like growths ( " bag of worms ").

Nervous system

CNS tumors ( for example, the Pilocytic astrocytoma with NF 1 and NF 2 in schwannoma ) and neurological symptoms as serious problems of neurofibromatosis. First of all tumors of the cranial nerves can make surgical intervention necessary. Auditory and trigeminal neuromas cause hearing loss especially, but also pain. A jugular foramen syndrome and hypoglossal tumors cause corresponding symptoms, an optic glioma, a unilateral blindness and tumors of the spinal roots can cause paralysis and pain. In addition, various neurological symptoms are described: difficulties at school, a rare epilepsy and hypothalamic hamartomas a precocious puberty. Sometimes Gliawucherungen cause in Aquäduktbereich, but also quite the neuromas an obstructive hydrocephalus. Particularly serious one takes the occurrence of seizures in patients with neurofibromatosis, as this can be considered a sign that a brain tumor developed.

Eye

The Lisch nodules of the eyes are considered to be a very useful diagnostic criterion, since they are found in almost all patients with neurofibromatosis type 1 for over 20 years. It is small, rounded, sharply defined and slightly elevated changes in the iris. They have a bright, yellowish to brownish tint. The number of these changes increases with the age of the patient. These melanocytes derived from benign tissue changes ( hamartomas ) of the iris have been described already in 1918 by Waardenburg. Their importance for the diagnosis of neurofibromatosis was discovered in 1937 by Karl Lisch. In 1981 the extremely large value of Lisch nodules was identified for the differential diagnosis of neurofibromatosis type 1 by the work of Vincent M. Riccardi and 1991 in a study by Marie Louise Lubs.

Bone

Skeletal changes occur in one third of patients and bring the neurofibromatosis patients to orthopedic surgeons.

Very often find spinal changes easier on kurzbogiger and kink -shaped scoliosis to extremely severe kyphoscoliosis due to maldevelopment of the vertebral body.

Bone cysts, hypertrophy, pathological fractures ( broken bones due to disease of the bone) and habitual dislocations ( recurrent joint dislocation ) make surgery necessary. Growth retardation and enlargement or asymmetry of the head provide for patients distressing symptoms dar. defects of Orbitahinterwand sometimes cause a pulsating exophthalmos and appearing to a tumor in the orbit.

Other characteristic change is the bending of a long bone fracture with tilt and consecutive non-union, most commonly in the tibia ( tibial nonunion Congenital ).

Diagnosis

As a cardinal symptoms or core symptoms is called features, by their common occurrence a disease is defined. In type 1 neurofibromatosis following two cardinal symptoms are described. More than 95 percent of patients with a secured neurofibromatosis type 1 have more than five café -au -lait spots, and more than 90 percent of patients find cutaneous tumors.

As clinical spectrum is referred to all the symptoms that a patient can get with a particular disease and their formation is brought into a causal connection with the illness, so is not merely coincidental. For most authors the following symptoms are considered mandatory clinical spectrum of neurofibromatosis type 1: Cafe -au -lait spots and cutaneous neurofibromas are among them. The detection of nodules Lisch possible depending on the study from 90 to 100 percent of the patients. In approximately 80 percent of patients there is a freckle -like pigmentation of the armpit. At 20 per cent of the patients are found plexiform large tumors. All other tumors ( spinal and peripheral neurofibromas, schwannomas of peripheral nerves et cetera ) are found in less than five percent of patients. Approximately one third of patients has also nonspecific symptoms such as problems at school (30 percent), short stature (15 percent), Macrozephalie ( 25 percent) and scoliosis ( 30 percent). Nonunions and epilepsy affect less than five percent of patients. Some of the patients developed a pheochromocytoma.

The diagnostic criteria include the symptoms that gets the vast majority of patients in the course of the disease. But not all patients develop all of these symptoms, but only a more or less random combination thereof. Doctors make a statistically sophisticated selection of average symptoms and use this as a diagnostic criteria to predict whether a person has a particular disease. The following table lists the diagnostic criteria for neurofibromatosis type 1 according to the NIH Consensus Development Conference of 1987:

Treatment

Since this is a genetic disease in neurofibromatosis type 1, is a therapy that aims to cure the underlying disorder, currently not possible. Therefore, the only treatment consists of surgical removal of the tumors and neurofibromas or, exceptionally, in which irradiation. One should, however, proceed very cautiously, because the operation of a neurofibroma may have the functional failure of the relevant nerves with permanent paralysis result. Tumors of the central nervous system may be located such that a surgical procedure without change to healthy tissue is not possible. There is also the possibility of surgery and radiation may promote growth of the tumors. Therefore, a very accurate risk - benefit assessment is required. There are usually only those changes removed that hold the risk of malignant development. Also, a severe neurological or orthopedic symptoms, serious cosmetic problems and an impending blindness constitutes grounds for an operation dar.

Forecast

Due to the mechanism described in the pathogenesis and molecular biology section, most of the symptoms of the disease develop in the course of time. In this sense, there is also a progression, with some tumors, such as the optic nerve glioma, may remain unchanged over a long time. With the variety of genetic findings is also associated with different symptoms and outcomes of the disease. The life expectancy of patients is normal in many cases, but the malignant tumors such as malignant peripheral nerve sheath tumors or glioblastomas occurs, the prognosis is correspondingly bad. Because of the autosomal dominant inheritance, a critical review of the desire for children is advised. There seem to occur fertility problems.