Neurofibromatosis von Recklinghausen type 1 (NF1) – clinical picture and molecular-genetics diagnostic
Authors:
Bořivoj Petrák 1; Šárka Bendová 2; Jiří Lisý 3; Josef Kraus 1; Tomáš Zatrapa 4; Marie Glombová 1; Josef Zámečník 5
Authors place of work:
Klinika dětské neurologie, 2. LF UK a FN Motol, Praha
1; Ústav biologie a lékařské genetiky, 2. LF UK a FN Motol, Praha
2; Klinika zobrazovacích metod, 2. LF UK a FN Motol, Praha
3; I. ortopedická klinika, 1. LF UK a FN Motol, Praha
4; Ústav patologie a molekulární medicíny, 2. LF UK a FN Motol, Praha
5
Published in the journal:
Čes.-slov. Patol., 51, 2015, No. 1, p. 34-40
Category:
Reviews Article
Summary
Neurofibromatosis von Recklinghausen type 1 (NF1) is a multisystem, autosomal dominant hereditary neurocutaneous disease characterized by skin, central and peripheral nervous system , eyes , bone, endocrine, gastrointestinal and blood vessel wall involvement. It has an estimated frequency of 1 in 3000. Neurofibromatosis type 1 is caused by mutations in the large NF1 gene located on chromosome 17q11.2, encoding the cytoplasmic protein neurofibromin. It is expressed in multiple cell types but is highly expressed in Schwann cells, oligodendrocytes, neurons, astrocytes and leukocytes. Neurofibromin is known to act as a tumor suppressor via Ras-GTPase activation, which causes down-regulation of cellular signaling via the Ras/mitogen-activated protein kinase (MAPK) pathway. Failure of this function is associated with a tendency to form tumors which are histologically hamartomas as well as benign tumors. Tumors of the central nervous system include low-grade gliomas (pilocytic astrocytomas grade I), especially optic pathway gliomas. They are often clinically asymptomatic. Other intracranial tumors are in the brain stem and also elsewhere in the brain and spinal cord. Hydrocephalus may be a complication of NF1 gliomas or due to stenosis of the distal part of the aqueduct Silvii. Cutaneous and subcutaneous neurofibromas or plexiform neurofibromas are localized in the peripheral nervous system. Plexiform neurofibromas have a significant lifetime risk of malignancy.
The clinical diagnosis of NF1 is defined by diagnostic criteria. The NF1 diagnosis is satisfied when at least two of the seven conditions are met. The method of direct DNA analysis of large NF1 gene (61 exons) is available. The results of studies of genotype - phenotype established few correlations. But predicting the disease by finding mutations is not currently possible. NF1 exhibits a wide range of variability of expression and complete penetrance, even within the same family. About half of cases are new mutations. The treatment of patients with neurofibromatosis is symptomatic. Central nervous system symptomatic low-grade gliomas are most often treated with chemotherapy. For plexiform neurofibromas surgical removal is currently the only treatment option.
Keywords:
NF1 – neurofibromin – glioma – neurofibroma – hydrocephalus - genetics
Zdroje
1. Von Recklinghausen FD. Ueber die multiplen Fibrome der Haut und ihre Beziehnung zu den multiplen Neuronomen. Berlin, Hirschwald; 1882.
2. Ferner RE, Huson SM, Thomas N, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet 2007; 44: 81-88.
3. Evans DGR. Neurofibromatosis type 2. In: Roach ES, MillerVS, editors. Neurocutaneous Disorders. Cambridge University Press,U.K; 2004: 50-59.
4. Petrák B, Plevová P, Novotný J, Foretová L. Neurofibromatosis von Recklinghausen. Klin Onkol 2009; 22(Suppl): 38–44.
5. Riccardi VM. Neurofibromatosis: Phenotype, Natural History, and Pathogenesis. 2nd ed. Baltimore: The Johns Hopkins University Press, 1992.
6. Tinschert S, Naumann I, Stegmann E, Buske A, Kaufmann D, Thiel G, Jeanne DE. Segmental neurofibromatosis is caused by somatic mutation of the neurofibromatosis type 1 (NF1) gene. Eur J Hum Genet 2000; 8(6): 455-459.
7. Ilenčíková D, Čižmárová M, Krajčiová A, Požgayová S, Rybárová A, Kovács L. Klinické dysmorfické syndromy s tumorigenézou. Klin Onkol 2012; 25(Suppl): 39–48.
8. Huson SM. The neurofibromatoses: classification, clinical featrures and genetic counselling. Kaufmann(ed): Neurofibromatoses, Monogr Hum Genet, Basel, Karger. Volume 16; 2008: 21-31.
9. Šnajderová M, Riccardi VM, Petrák B, et. al. The importance of advanced parental age in the origin of neurofibromatosis type1. Am J Med Genet Part A 2012; 158A: 519-523.
10. Upadhyaya M. NF1 Gene Structure and NF1 Genotype/Phenotype Correlations. Kaufmann(ed): Neurofibromatoses, Monogr Hum Genet, Basel, Karger. Vol. 16; 2008: 46-62.
11. Trovo-Marqui AB, Tajara EH. Neurofibromin: a general outlook. Clin Genet 2006; 70(1): 1-13.
12. Le LQ, Parada LF. Tumor microenvironment and neurofibromatosis type I: connecting the GAPs. Oncogene 2007; 26(32): 4609-4616.
13. McClatchey AI, Cichowski K. Mouse models of neurofibromatosis. Biochim Biophys Acta 2001; 1471(2): 73-80.
14. Viskochil D, White R, Cawthon R. The neurofibromatosis type 1 gene. Annu Rev Neurosci 1993; 16: 183-205.
15. Zhu Y, Romero MI, Ghosh P, et al. Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain. Genes Dev 2001; 15(7): 859-876.
16. Welti S. Structure and Function of Neurofibromin. Kaufmann(ed): Neurofibromatoses, Monogr Hum Genet, Basel, Karger. Volume 16; 2008: 113-128.
17. Lau N, Feldkamp MM, Roncari L, et al. Loss of neurofibromin is associated with activation of RAS/MAPK and PI3-K/AKT signaling in a neurofibromatosis 1 astrocytoma. J Neuropathol Exp Neurol 2000; 59(9): 759-767.
18. Serra E, Rosenbaum T, Nadal M, et al. Mitotic recombination effects homozygosity for NF1 germline mutations in neurofibromas. Nat Genet 2001; 28(3): 294-296.
19. Cooper DN, Ball EV, Stenson PD, Phillips AD, Shaw K, Mort ME. 2012: www.hgmd.org.
20. Shen MH, Harper PS, Upadhyaya M. Molecular genetics of neurofibromatosis type 1 (NF1). J Med Genet 1996; 33(1): 2-17.
21. Fahsold R, Hoffmeyer S, Mischung C, et al. Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet 2000; 66(3): 790-818.
22. Ainsworth P, Rodenhiser D, Stuart A, Jung J. Characterization of an intron 31 splice junction mutation in the neurofibromatosis type 1 (NF1) gene. Hum Mol Genet 1994; 3(7): 1179-1181.
23. Stark M, Assum G, Krone W. A small deletion and an adjacent base exchange in a potential stem-loop region of the neurofibromatosis 1 gene. Hum Genet 1991; 87(6): 685-687.
24. Shen MH, Harper PS, Upadhyaya M. Neurofibromatosis type 1 (NF1): the search for mutations by PCR-heteroduplex analysis on Hydrolink gels. Hum Mol Genet 1993; 2(11): 1861-1864.
25. Harder A, Titze S, Herbst L, et al. Monozygotic twins with neurofibromatosis type 1 (NF1) display differences in methylation of NF1 gene promoter elements, 5‘ untranslated region, exon and intron 1. Twin Res Hum Genet 2010; 13(6): 582-594.
26. Upadhyaya M, Huson SM, Davies M, et al. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet 2007; 80(1): 140-151.
27. De Raedt T, Brems H, Lopez-Correa C, Vermeesch JR, Marynen P, Legius E. Genomic organization and evolution of the NF1 microdeletion region. Genomics 2004; 84(2): 346-360.
28. Lazaro C, Gaona A, Estivill X. Two CA/GT repeat polymorphisms in intron 27 of the human neurofibromatosis (NF1) gene. Hum Genet 1994; 93(3): 351-352.
29. Wimmer K, Roca X, Beiglbock H, et al. Extensive in silico analysis of NF1 splicing defects uncovers determinants for splicing outcome upon 5‘ splice-site disruption. Hum Mutat 2007; 28(6): 599-612.
30. Natiomal Institute of Health Consensus Development Conference. Neurofibromatosis: Conference Statement. Arch Neurol Chicago 1988; 45: 575-578.
31. Goldstein J, Gutmann D. Neurofibromatosis type 1. In: Roach ES, MillerVS, ed. Neurocutaneous Disorders. Cambridge University Press, U.K.; 2004, pp. 42-49.
32. Maria BL, Menkes JH. Neurocutaneous Syndromes. In: Menkes JH, Sarnat HB, Maria BL eds. Child Neurology. 7th ed. Lippincott Williams Wilkins, Philadelphia; 2005, pp. 803-828.
33. Evans DGR, Baser ME, McGaughran J, Sharif S, Howard E, Moran A. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet 2002; 39: 311-314.
34. Leisti EL. Radiologic findings of the head and spine in neurofibromatosis 1 (NF1) in Northern Finland. Academic Dissertation. Oulu, Finland: University of Oulu and Oulu Univestity Hospital 2003.
35. Brems, H., Pasmant, E., Van Minkelen, R., Wimmer, K., Upadhyaya, M., Legius, E., Messiaen, L. Review and update of SPRED1 mutations causing Legius syndrome. Hum Mutat 2012; 33: 1538-1546.
36. De Luca A, Bottillo I, Sarkozy A, et al. NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome. Am J Hum Genet 2005; 77: 1092-1101.
37. Kalužová M, Petrák B., Lisý J., Vaculík M., Bendová Š., Komárek V. Idiopatická stenóza akveduktu a porucha vývoje řeči u dětí s neurofibromatosis von Recklinghausen typ 1 – dvě kazuistiky. Cesk Slov Neurol N 2012; 75/108(5): 633-636.
38. Petrák B, Bendová S, Seeman T, Klein T, Lisý J, Zatrapa T, Maříková T. Mid-aortic syndrome with renovascular hypertension and multisystem involvement in a girl with familiar neurofibromatosis von Recklinghausen type 1. Neuroendocrinol Lett 2007; 28(6): 734-738.
39. Petrák B, Lisý J, Kalužová M, Kraus J. Význam hypersignálních ložisek v T2 vážených obrazech na MRI vyšetření mozku pro stanovení diagnosy neurofibromatosis von Recklinghausen typ 1. Cesk-slov pediat 2010; 65(5): 326-327.
40. DiPaolo DP, Zimmerman RA, Rorke LB, Zackai EH, Bilaniuk LT, Yachnis AT. Neurofibromatosis type 1: pathologic substrate of high‑signal- intensity foci in the brain. Radiology 1995; 195(3): 721–724.
41. Ferraz-Filho JR, José da Rocha A, Muniz MP, Souza AS, Goloni-Bertollo EM, Pavarino-Bertelli EC. Unidentified bright objects in neurofibromatosis type 1: conventional MRI in the follow-up and correlation of microstructural lesions on diffusion tensor images. Eur J Paediatr Neurol 2012; 16(1): 42-47.
42. Matsuda K, Shimada A, Yoshida N, et al. Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations. Blood 2007; 109(12): 5477-5480.
Štítky
Anatomical pathology Forensic medical examiner ToxicologyČlánok vyšiel v časopise
Czecho-Slovak Pathology
2015 Číslo 1
Najčítanejšie v tomto čísle
- Neurofibromatosis von Recklinghausen type 1 (NF1) – clinical picture and molecular-genetics diagnostic
- Pathological evaluation of colorectal cancer specimens: advanced and early lesions
- Mammary fibroadenoma with pleomorphic stromal cells
- Small cell type (Ewing-like) clear cell sarcoma of soft parts: a case report