Neurofibromatosis type 1
| Classification according to ICD-10 | |
|---|---|
| Q85.0 | Neurofibromatosis (not malignant) - von Recklinghausen disease |
| ICD-10 online (WHO version 2019) | |
The neurofibromatosis type 1 (short: NF1 ), also Von Recklinghausen's disease , Recklinghausen's disease (named after its discoverer Friedrich Daniel von Recklinghausen ) or peripheral neurofibromatosis is an autosomal - dominant and monogenic inherited multisystem disease.
About 50 percent of those affected have a new mutation. NF1 primarily affects the skin and nervous system . It is therefore assigned to neurocutaneous diseases ( phakomatoses ). Typical changes on the skin are café-au-lait spots and neurofibromas . As café-au-lait spots referred to milchkaffee colored hyperpigmentation of the skin. They are at the level of the skin, can occur in all people and are harmless. They are more common in people with NF1. As neurofibromas referred to benign tumors derived from the cells of the Schwann sheaths smaller in the skin extending nerve fibers originate. In the central nervous system (CNS), tumors in various locations occur more frequently . Due to the disease, patients may be mentally disabled ( gifted ) and suffer from epileptic seizures . In addition, the eyes (resulting in poor eyesight) and bones are also often affected. Puberty can be early or late. A neurofibromatosis is a change in a gene caused, which normally inhibit the cell division influences. There is therefore excessive tissue proliferation and thus the typical changes. The diagnosis is usually made in childhood on the basis of the clinical picture. Since Recklinghausen's disease is a genetic disease, therapy that eliminates its cause is currently not possible. Therefore, only changes are treated that are disruptive or dangerous for the patient. Another known form of neurofibromatosis is neurofibromatosis type 2 (NF2), which occurs much less frequently and is caused by a mutation in another gene.
history
A rather anecdotal first description can be found in Robert William Smith 1849. Friedrich Daniel von Recklinghausen presented the first precise clinical and pathological characterization in 1882. Alex Thomsen published the first statistical data and a detailed bibliography around 1900. Joseph Merrick , the so-called "Elephant Man", has long been considered an example of the disfiguring effects of Recklinghausen's disease. His life in Victorian England was the basis for books and films, especially David Lynch's The Elephant Man . Merrick's severe distortions shaped the widespread misconceptions about the monstrosity of patients with neurofibromatosis type 1. According to a DNA analysis in 2003, Merrick suffered from Proteus syndrome , with an additional disease from neurofibromatosis type 1 being probable. The oldest written descriptions of the disease that have survived date from the 13th century.
Incidence, inheritance, and epidemiology
It is estimated that there are around 30 to 40 sick people per 100,000 inhabitants, which corresponds to an expectation of one affected child per 2500 to 3300 births. In half of the cases it is assumed that a new mutation leads to changes in the genetic make-up. All previous observations confirm the autosomal dominant inheritance , which means that an affected parent has a 50 percent chance of passing the disease on to their children. There are no different frequencies in different regions of the world or among members of other ethnic groups. However, men get sick a little more often than women. The high rate of new mutations is explained by the fact that the NF-1 gene is very large and thus offers a lot of target for genetic changes.
Pathogenesis and Molecular Biology
Neurofibromatosis type 1 was one of the first hereditary tumors whose genetics could be elucidated. The neurofibromatosis type 1 locus is located on chromosome 17 gene locus q11.2. It is complex and possibly codes for a protein that modulates the intracellular signal pathway . The neurofibromatosis type 1 gene locus spans around 400,000 base pairs . In an intron of more than 40,000 base pairs in this locus, three genes are found in the opposite reading direction: OMPG codes for a membrane-bound glycoprotein of oligodendrocyte myelin , EVI2A and EVI2B code for viral insertion sequences . Translocations (1.17) and (17.22), deletions , insertions and point mutations have been described at the neurofibromatosis type 1 locus . The more than 50 exons of the gene code for various 9 to 11 kB transcripts . An open reading frame of the genomic locus comprising approx. 7800 base pairs allows the derivation of a protein with approx. 2500 amino acids . The neurofibromatosis type 1 peptide (neurofibromin) shows sequence homologies with the mammalian GAP ( GTPase- activating protein) and the IRA1 and IRA2 genes of yeast . The GAP-related domain of the NF-1 peptide binds to the “ras p21” protein in vitro. The NF-1 catalytic domain stimulates the GTPase activity of ras p21. When GTPases are activated by their (individual) GAP, they hydrolyse the bound GTP to GDP and as such are no longer able to stimulate their effector. In the case of ras p21, this effector is a mitogenic (cell division-stimulating) signal mediated via the phosphatidylinositol pathway. Defective GAPs can therefore no longer switch off a mitogenic signal, the cells proliferate in an uncontrolled manner.
The microdeletion syndrome 17q11.2 can be viewed as a special form of this type 1 neurofibromatosis.
pathology
Tumors
In neurofibromatosis, a number of tumors that affect both the central nervous system and can occur outside of it occur more frequently.
Nervous system tumors
Neurofibromas
Particularly characteristic of the disease is the occurrence of neurofibromas , which, in contrast to sporadic neurofibromas, are often neurofibromas of the skin (dermal neurofibromas) or so-called plexiform neurofibromas. Dermal neurofibromas are benign, easily demarcated tumors located under the skin, originating from small cutaneous nerve branches and consisting of Schwann cells and fibroblast- like cells. Plexiform neurofibromas infiltrate diffusely larger nerve branches and thus lead to a piston-shaped swelling. In contrast to normal neurofibromas, the risk of malignant degeneration is significantly increased by around ten percent.
Malignant peripheral nerve sheath tumors
Malignant peripheral nerve sheath tumors occur in neurofibromatosis already in younger age and can histologically in skeletal muscle reminiscent rhabdomyoblastische or glands similar contain glandular elements. Such tumors, which are also called Triton tumors, are highly characteristic of neurofibromatosis type 1.
Gliomas
The majority of the gliomas occurring in neurofibromatosis type 1 are the benign pilocytic astrocytomas located in the area of the optic nerve (optic nerve) , which are also known as optic gliomas in this location. In neurofibromatosis type 1, optic gliomas typically occur bilaterally and thus affect both optic nerves. Optic gliomas in patients with type 1 neurofibromatosis can have a static course for many years. Other gliomas that are more common in neurofibromatosis type 1 are diffuse astrocytomas and malignant glioblastoma .
Tumors outside the nervous system
The incidence of pheochromocytomas , tumors of the adrenal medulla , is increased. The same applies to other rare tumors such as rhabdomyosarcomas , juvenile xanthogranuloma , gastrointestinal stromal tumors (GIST) , medullary thyroid carcinomas and chronic myelomonocytic leukemia .
Pigment disorders
Café-au-lait spots, freckling in the area of both armpits (so-called axillary freckling ) and Lisch nodules are due to changes in the melanocytes of the skin. Café-au-lait spots are often already present at birth and become more frequent and larger in the course of childhood. Freckling, a type of freckle formation in the armpits and the sides of the upper body, usually occurs from around 5-7 years of age. Lisch nodules often only appear during or after puberty. Histologically, the ratio of melanocytes to keratinocytes, which is already shifted in the unaffected skin in neurofibromatosis type 1, is further increased in the area of café-au-lait spots and freckling. The Lisch nodules that appear in the area of the iris of the eye are histologically small pigmented hamartomas .
Changes in the bones and blood vessels
NF1 can have serious effects on bone formation. Some of the disorders are already present in those affected at birth. These include dysplasia of the sphenoid wing , in which the eye socket is deformed. Another congenital bone disorder affects the long tubular bones of the extremities, which can be deformed or prone to fractures and can form pseudo-joints. Fibromuscular dysplasia can occur in the area of the blood vessels , which can particularly affect the renal arteries.
In the age range up to 12 years, deformation of the vertebral bodies can occur, which can lead to severe scoliosis . An early and regular presentation to a specialist familiar with NF1 is therefore advisable.
Clinical manifestations
skin
Café-au-lait spots and changes in the color of the armpit are noticeable skin manifestations. Café-au-lait spots are found in more than 95 percent of the cases in patients with Recklinghausen neurofibromatosis. About 80 percent have more than six large hyperpigmented areas. However, café-au-lait stains also occur in around ten percent of the unaffected population. These changes are large (up to several centimeters), sharp and irregularly defined light to dark brown spots that are often noticeable at birth or in childhood. They are distributed on the body with no recognizable order. There is an increase in melanocytes .
The so-called freckle ( freckle = freckles, spots, speckles) is a freckle-like discoloration on parts of the body that are normally not exposed to sunlight. These changes are most noticeable in the armpit and groin region. This is observed from around 10 years of age. Since freckling occurs in around 90 percent of patients with neurofibromatosis type 1, it is a diagnostically groundbreaking phenomenon. In addition, diffuse color changes of the trunk ( lentiginosis ) are described, which also occur more frequently in the area of the axillae.
Neurofibromas are tumors of the peripheral nervous system that are particularly noticeable in the skin area. They typically occur cutaneous (skin = tissue of the skin), subcutaneous (subcutaneous = subcutaneous tissue) or as plexiform neurofibromas. Cutaneous neurofibromas typically form at the onset of puberty. Plexiform neurofibromas are often congenital. Patients' skin can be covered with up to 10,000 tumors of various sizes over time. They vary in diameter from a few millimeters to several centimeters per lesion. The neurofibromas can lie below the surface and then stand out as a hilly surface structure of the skin. Others can sit hemispherically on the skin or stick in the form of a sack. It is noticeable that they move deeper when pressed, which is known as the buttonhole phenomenon or the bell button phenomenon. With this simple experiment one can very easily distinguish a neurofibroma from a lipoma . The tumors are usually skin colored, but can also appear reddish, bluish, or purple in color. The cutaneous neurofibromas have a soft, homogeneous consistency. As NF1 is progressive, the number of neurofibromas increases throughout life.
The deeper subcutaneous neurofibromas are thick thickenings that arise from the peripheral nerves. Since the growths also press on the nerves themselves, they often lead to pain and changes in sensation.
The plexiform tumors are not infrequently located on the face, neck, hip and lower leg. They sometimes reach an enormous size and show the unusual tactile findings of multiple cord-shaped growths ("sack full of worms").
Nervous system
CNS tumors (for example pilocytic astrocytoma in NF 1 and schwannoma in NF 2 ) and neurological symptoms are serious problems of neurofibromatosis. In particular, tumors of the cranial nerves can make surgical interventions necessary. Acoustic and trigeminal neuromas , which predominantly occur in NF 2, cause hearing loss in particular, but also pain. A foramen jugular 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: Affected children often have a low IQ, ADD or ADHD, problems with self-organization, motor weaknesses in both fine and gross motor skills, resulting in school difficulties , rarely epilepsy and, with hypothalamic hamartomas, puberty Precox . If epileptic seizures occur in patients with neurofibromatosis, this can be taken as a sign that a brain tumor is developing.
eyes
The Lisch nodules of the eyes are considered a very helpful diagnostic criterion, as they are found in almost all patients with neurofibromatosis type 1 over 20 years of age. These are small, rounded, sharply delimited and slightly raised changes in the iris . They have a light, yellowish to brownish hue. The number of these changes increases with the age of the patient. These benign tissue changes ( hamartomas ) of the iris, which originate from melanocytes , were described by Waardenburg as early as 1918 . Its importance for the diagnosis of neurofibromatosis was discovered by Karl Lisch in 1937. In 1981, through the work of Vincent M. Riccardi and in 1991 through a study by Marie Louise Lubs, the extraordinarily great value of Lisch nodules for the differential diagnosis of neurofibromatosis type 1 was shown.
bone
Skeletal changes occur in a third of patients and take the neurofibromatosis patients to the orthopedic surgeon.
Changes in the spine, ranging from simple to short-arched and kink-shaped scoliosis to extremely pronounced kyphoscoliosis due to incorrect development of the vertebral bodies, are very common .
Bone cysts, hypertrophies, pathological fractures (broken bones due to a disease of the bone) and habitual dislocations (recurring joint dislocation) make surgical interventions necessary. Short stature and enlargement ( megalencephaly ) or asymmetry of the head are stressful symptoms for the patient. Defects in the posterior wall of the orbit sometimes cause a pulsating exophthalmos and thus simulate a tumor in the eye socket.
Another characteristic change is the bending of a long tubular bone with a tendency to fracture and subsequent pseudarthrosis , most often in the tibia ( congenital tibial osteoarthritis ).
diagnosis
Cardinal symptoms or core symptoms are characteristics whose common occurrence defines a disease. In neurofibromatosis type 1, the following two cardinal symptoms are described. More than 95 percent of patients with confirmed neurofibromatosis type 1 have more than five café-au-lait spots, and cutaneous tumors are found in more than 90 percent of patients.
The clinical spectrum is used to describe all symptoms that a patient with a certain disease can get and the emergence of which is causally related to the disease, i.e. is not just coincidental. Most authors consider the following symptoms to be the mandatory clinical spectrum of neurofibromatosis type 1: café-au-lait spots and cutaneous neurofibromas are among them. Lisch nodules can be detected in 90 to 100 percent of patients, depending on the study. Freckle-like pigmentation of the armpit is found in around 80 percent of patients. Large plexiform tumors are found in 20 percent of patients. All other tumors (spinal and peripheral neurofibromas , schwannomas of the peripheral nerves, etc.) are found in less than five percent of patients. About a third of the patients also have unspecific symptoms such as school problems (30 percent), short stature (15 percent), macrocephaly (25 percent) and scoliosis (30 percent). Nonunion and epilepsy occur in less than five percent of patients. Some of the patients develop a pheochromocytoma .
The diagnostic criteria include the symptoms that the vast majority of patients get in the course of the disease. The following table gives the diagnostic criteria for neurofibromatosis type 1 according to the NIH Consensus Development Conference of 1987:
|
Diagnostic criteria (two or more applicable criteria) |
|
| 1) |
Six café-au-lait spots (larger than 5 mm before puberty, then larger than 15 mm) |
| 2) | Axillary or inguinal pigmentation |
| 3) |
Two or more neurofibromas or one plexiform neurofibroma |
| 4) | A first-degree relative with neurofibromatosis type 1 |
| 5) | Two or more Lisch nodules |
| 6) | Bone lesions |
treatment
Since neurofibromatosis type 1 is a genetic disease, a therapy that aims to cure the underlying disorder is currently not possible. The only treatment option is the surgical removal of the neurofibromas and tumors or, in exceptional cases, irradiation. However, one should proceed very cautiously, because the operation of a neurofibroma can result in the functional failure of the nerve concerned with permanent paralysis. Radiation can trigger an increased growth of the tumors. Tumors of the central nervous system can be located in such a way that an operative procedure without changes to healthy tissue is not possible. There is also the possibility that surgery and radiation could encourage tumor growth. A very precise risk-benefit assessment is therefore required. Only changes that are at risk of malignant development are usually removed. A PET scan can be helpful here . The diagnosis of malignant peripheral nerve sheath tumor should be considered when a patient develops pain that cannot be explained, the size of a neurofibroma increases rapidly and / or its texture changes. Severe neurological or orthopedic symptoms, serious cosmetic problems and impending blindness are also reasons for an operation.
forecast
Due to the mechanism described in the Pathogenesis and Molecular Biology section, most symptoms of the disease take time to develop. In this sense, there is also progression , whereby some tumors, such as the optic glioma, can remain unchanged over a long period of time. With the variety of genetic findings, there are also different symptoms and courses of the disease. The life expectancy of the patient is normal in many cases. If malignant tumors such as malignant peripheral nerve sheath tumors or glioblastomas occur , however, life expectancy is significantly reduced. Because of the autosomal dominant inheritance, as with other hereditary diseases, genetic counseling is useful if you are trying to have children. Fertility disorders also seem to occur.
Individual evidence
- ↑ M. Deckert, G. Reifenberger, U.-N. Riede, W. Schlote, DR Thal, OD Wiestler: nervous system. In: Ursus-Nikolaus Riede, Martin Werner, Hans-Eckart Schäfer (eds.): General and special pathology. 5th edition. Stuttgart, 2004, p. 1104.
- ↑ Bruce Ponder: Neurofibromatosis gene cloned. In: Nature . Volume 346, 1990, p. 703. PMID 2117711
- ↑ David Viskochil: Deletions and a Translocation Interrupt a Cloned Gene at the Neurofibromatosis Type 1 Locus. In: Cell . Vol. 62, 1990, pp. 187-192. PMID 1694727
- ↑ Margaret R. Wallace: Type 1 Neurofibromatosis Gene, Identification of a Large Transcript Disrupted in Three NF1 Patients. In: Science . Volume 249, 1990, pp. 181-186. PMID 2134734
- ↑ Toru Nishi: Differential expression of two types of the neurofibromatosis type 1 (NF1) gene transcripts related to neuronal differentiation. In: Oncogene . Volume 6, 1991, pp. 1555-1599. PMID 1923522
- ↑ Gangfeng Xu: The Neurofibromatosis Type 1 Gene Encodes a Protein Related to GAP. In: Cell. Vol. 62, 1990, pp. 599-608. PMID 2116237
- ↑ Roymarie Ballester: The NF1 locus Encodes a protein Functionally Related to Mammalian GAP and IRA Yeast protein. In: Cell. Vol. 63, 1990, pp. 851-859. PMID 2121371
- ↑ George A. Martin: The GAP-related Domain of the Neurofibromatosis Type 1 Gene Product interacts with ras p21. In: Cell. Vol. 63, 1990, p. 843. PMID 2121370
- ↑ Gangfeng Xu: The Catalytic Domain of the Neurofibromatosis Type 1 Gene Product Stimulates ras GTPase and Complements ira Mutants of S. cerevisiae. In: Cell. Vol. 63, 1990, pp. 835-841. PMID 2121369
- ↑ Deimling & Perry: Neurofibromatosis type 1. In: WHO classification of central nervous system tumors. Lyon, IAR Press, 2007.
- ^ A b Anthony Killen, Emanuel Rubin, David Strayer: Developmental and Genetic Diseases. In: Raphael Rubin, David Strayer (eds.): Rubin's Pathology. 5th edition. Philadelphia, 2008, p. 201.
- ^ PJ Waardenburg: Heterochrome en melanosis. In: Nederlands tijdschrift voor geneeskunde. Volume 62, 1918, pp. 1453-1455.
- ^ VM Riccardi: Neurofibromatosis: an overview and new directions in clinical investigations. In: Advances in neurology. Volume 29, 1981, pp. 1-9, ISSN 0091-3952 . PMID 6798831 .
- ^ Marie-Louise Lubs: Lisch-Nodules in Neurofibromatosis Type I. In: The New England journal of medicine . Volume 324, 1991, p. 1264. PMID 1901624
- ↑ F. Hefti: Pediatric Orthopedics in Practice. Springer 1998, ISBN 3-540-61480-X .
- ↑ Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. In: Archives of Neurology . Volume 45, Number 5, May 1988, pp. 575-578, ISSN 0003-9942 . PMID 3128965 .
- ↑ T. Derlin, J. Salamon, P. Bannas, JD Busch, J. Herrmann: Intratumoral heterogeneity of tracer uptake in the F-18 FDG PET / CT as a characteristic of malignant peripheral nerve sheath tumors in patients with neurofibromatosis type 1 . In: RöFo - Advances in the field of X-rays and imaging processes . tape 185 , S 1, April 2013, ISSN 1438-9029 , p. VO310_2 , doi : 10.1055 / s-0033-1346408 ( thieme-connect.de [accessed on July 30, 2020]).
- ↑ Deutscher Ärzteverlag GmbH, editorial office of the Deutsches Ärzteblatt: Tumors of peripheral nerves: Does it make sense to supplement? November 8, 2002, accessed July 30, 2020 .
- ↑ Neurofibromatosis Fact Sheet. ( Memento of the original from November 19, 2016 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. National Institute of Neurological Disorders and Stroke, accessed March 25, 2012.
literature
Books
- Klaus Poeck, Werner Hacke: Neurology. 11th edition. Springer, Berlin 2001, ISBN 3-540-41345-6 .
- Peter Fritsch: Dermatology and Venereology. 2nd Edition. Springer, Berlin 2003, ISBN 3-540-00332-0 .
- Lewis P. Rowland: Merrits Textbook of Neurology . Williams & Wilkins, Baltimore 1995, ISBN 0-683-07400-8 .
- VM Riccardi (Ed.): Neurofibromatosis, phenotype, natural history and pathogenesis. Johns Hopkins University Press, Baltimore 1986, 1992, ISBN 0-8018-4348-0 .
- Raymond D. Adams: Neurocutaneous Diseases. In: TB Fitzpatrick, AZ Eisen, K. Wolff (Ed.): Dermatology in General Medicine. 2 volumes. McGraw-Hill, New York 1987, 1993, 2003, ISBN 0-07-138076-0 (set)
Articles in magazines
- B. Castle: Evaluation of genotype-phenotype correlations in neurofibromatosis type 1. In: Journal of Medical Genetics . BMJ Publishing Group, London 40.2003,10 (Oct), 109th PMID 14569132 (freely accessible review article)
