Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1992 Sep;51(3):486–496.

Neurofibromatosis type 2 appears to be a genetically homogeneous disease

Steven A Narod, Dilys M Parry, Jillian Parboosingh, Gilbert M Lenoir, Martin Ruttledge, Georges Fischer, Roswell Eldridge, Robert L Martuza, Marina Frontali, Jonathan Haines, James F Gusella, Guy A Rouleau
PMCID: PMC1682700  PMID: 1496982

Abstract

Neurofibromatosis type 2 (NF2) is an autosomal dominant syndrome characterized by the development of vestibular schwannomas and other tumors of the nervous system, including cranial and spinal meningiomas, schwannomas, and ependymomas. The presence of bilateral vestibular schwannomas is sufficient for the diagnosis. Skin manifestations are less common than in neurofibromatosis type 1 (NF1; von Recklinghausen disease). The apparent clinical distinction between NF1 and NF2 has been confirmed at the level of the gene locus by linkage studies; the gene for NF1 maps to chromosome 17, whereas the gene for NF2 has been assigned (in a single family) to chromosome 22. To increase the precision of the genetic mapping of NF2 and to determine whether additional susceptibility loci exist, we have performed linkage analysis on 12 families with NF2 by using four polymorphic markers from chromosome 22 and a marker at the NF1 locus on chromosome 17. Our results confirm the assignment of the gene for NF2 to chromosome 22 and do not support the hypothesis of genetic heterogeneity. We believe that chromosome 22 markers can now be used for presymptomatic diagnosis in selected families. The NF2 gene is tightly linked to the D22S32 locus (maximum lod score 4.12; recombination fraction 0). A CA-repeat polymorphism at the CRYB2 locus was the most informative marker in our families (lod score 5.99), but because the observed recombination fraction between NF2 and CRYB2 was 10 cM, predictions using this marker will need to be interpreted with caution.

Full text

PDF
488

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allen J. C., Eldridge R., Young D. Early-onset neuroma: genetic, clinical and nosologic aspects. Birth Defects Orig Artic Ser. 1974;10(10):171–184. [PubMed] [Google Scholar]
  2. Alliez J., Masse J. L., Alliez B. Tumeurs bilatérales de l'acoustique et maladie de recklinghausen observées dans plusieurs générations. Considérations sur les tumeurs de l'acoustique héréditaires. Rev Neurol (Paris) 1975 Aug;131(8):545–558. [PubMed] [Google Scholar]
  3. Barker D., Wright E., Nguyen K., Cannon L., Fain P., Goldgar D., Bishop D. T., Carey J., Baty B., Kivlin J. Gene for von Recklinghausen neurofibromatosis is in the pericentromeric region of chromosome 17. Science. 1987 May 29;236(4805):1100–1102. doi: 10.1126/science.3107130. [DOI] [PubMed] [Google Scholar]
  4. Bodmer W. F., Bailey C. J., Bodmer J., Bussey H. J., Ellis A., Gorman P., Lucibello F. C., Murday V. A., Rider S. H., Scambler P. Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature. 1987 Aug 13;328(6131):614–616. doi: 10.1038/328614a0. [DOI] [PubMed] [Google Scholar]
  5. Cawthon R. M., Weiss R., Xu G. F., Viskochil D., Culver M., Stevens J., Robertson M., Dunn D., Gesteland R., O'Connell P. A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell. 1990 Jul 13;62(1):193–201. doi: 10.1016/0092-8674(90)90253-b. [DOI] [PubMed] [Google Scholar]
  6. Conneally P. M., Edwards J. H., Kidd K. K., Lalouel J. M., Morton N. E., Ott J., White R. Report of the Committee on Methods of Linkage Analysis and Reporting. Cytogenet Cell Genet. 1985;40(1-4):356–359. doi: 10.1159/000132186. [DOI] [PubMed] [Google Scholar]
  7. Dumanski J. P., Carlbom E., Collins V. P., Nordenskjöld M., Emanuel B. S., Budarf M. L., McDermid H. E., Wolff R., O'Connell P., White R. A map of 22 loci on human chromosome 22. Genomics. 1991 Nov;11(3):709–719. doi: 10.1016/0888-7543(91)90079-t. [DOI] [PubMed] [Google Scholar]
  8. Dutcher P. O., Jr, House W. F., Hitselberger W. E. Early detection of small bilateral acoustic tumors. Am J Otol. 1987 Jan;8(1):35–38. [PubMed] [Google Scholar]
  9. Fischer G. Le neurinome bilatéral de l'acoustique. Rev Laryngol Otol Rhinol (Bord) 1979 Jan-Feb;100(1-2):97–101. [PubMed] [Google Scholar]
  10. Gusella J. F., Wexler N. S., Conneally P. M., Naylor S. L., Anderson M. A., Tanzi R. E., Watkins P. C., Ottina K., Wallace M. R., Sakaguchi A. Y. A polymorphic DNA marker genetically linked to Huntington's disease. Nature. 1983 Nov 17;306(5940):234–238. doi: 10.1038/306234a0. [DOI] [PubMed] [Google Scholar]
  11. Haines J. L., Amos J., Attwood J., Bech-Hansen N. T., Burley M., Conneally P. M., Connor J. M., Fahsold R., Flodman P., Fryer A. Genetic heterogeneity in tuberous sclerosis. Study of a large collaborative dataset. Ann N Y Acad Sci. 1991;615:256–264. doi: 10.1111/j.1749-6632.1991.tb37767.x. [DOI] [PubMed] [Google Scholar]
  12. Hall J. M., Lee M. K., Newman B., Morrow J. E., Anderson L. A., Huey B., King M. C. Linkage of early-onset familial breast cancer to chromosome 17q21. Science. 1990 Dec 21;250(4988):1684–1689. doi: 10.1126/science.2270482. [DOI] [PubMed] [Google Scholar]
  13. Kaiser-Kupfer M. I., Freidlin V., Datiles M. B., Edwards P. A., Sherman J. L., Parry D., McCain L. M., Eldridge R. The association of posterior capsular lens opacities with bilateral acoustic neuromas in patients with neurofibromatosis type 2. Arch Ophthalmol. 1989 Apr;107(4):541–544. doi: 10.1001/archopht.1989.01070010555030. [DOI] [PubMed] [Google Scholar]
  14. Kanter W. R., Eldridge R., Fabricant R., Allen J. C., Koerber T. Central neurofibromatosis with bilateral acoustic neuroma: genetic, clinical and biochemical distinctions from peripheral neurofibromatosis. Neurology. 1980 Aug;30(8):851–859. doi: 10.1212/wnl.30.8.851. [DOI] [PubMed] [Google Scholar]
  15. Kimberling W. J., Fain P. R., Kenyon J. B., Goldgar D., Sujansky E., Gabow P. A. Linkage heterogeneity of autosomal dominant polycystic kidney disease. N Engl J Med. 1988 Oct 6;319(14):913–918. doi: 10.1056/NEJM198810063191405. [DOI] [PubMed] [Google Scholar]
  16. Koos W. T., Böck F. W. Experiences with the microneurosurgical treatment of bilateral acoustic tumors. Neurochirurgia (Stuttg) 1972 Sep;15(5):159–166. doi: 10.1055/s-0028-1090535. [DOI] [PubMed] [Google Scholar]
  17. Krapcho K., Nakamura Y., Fujimoto E., Eldridge R., Leppert M., O'Connell P., Lathrop G. M., Lalouel J. M., White R. Isolation and mapping of a polymorphic DNA sequence (pEFZ31) on chromosome 22 [D22S32]. Nucleic Acids Res. 1988 Jun 10;16(11):5221–5221. doi: 10.1093/nar/16.11.5221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Landau K., Dossetor F. M., Hoyt W. F., Muci-Mendoza R. Retinal hamartoma in neurofibromatosis 2. Arch Ophthalmol. 1990 Mar;108(3):328–329. doi: 10.1001/archopht.1990.01070050026011. [DOI] [PubMed] [Google Scholar]
  19. Lathrop G. M., Lalouel J. M., Julier C., Ott J. Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci U S A. 1984 Jun;81(11):3443–3446. doi: 10.1073/pnas.81.11.3443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Marineau C., Rouleau G. A. Dinucleotide repeat polymorphism at the human CRYB2 gene locus (22q11.2). Nucleic Acids Res. 1992 Mar 25;20(6):1430–1430. [PMC free article] [PubMed] [Google Scholar]
  21. Martuza R. L., Eldridge R. Neurofibromatosis 2 (bilateral acoustic neurofibromatosis). N Engl J Med. 1988 Mar 17;318(11):684–688. doi: 10.1056/NEJM198803173181106. [DOI] [PubMed] [Google Scholar]
  22. Mayfrank L., Wullich B., Wolff G., Finke J., Gouzoulis E., Gilsbach J. M. Neurofibromatosis 2: a clinically and genetically heterogeneous disease? Report on 10 sporadic cases. Clin Genet. 1990 Nov;38(5):362–370. doi: 10.1111/j.1399-0004.1990.tb03596.x. [DOI] [PubMed] [Google Scholar]
  23. McKennan K. X., Bard A. Neurofibromatosis type 2: report of a family and review of current evaluation and treatment. Laryngoscope. 1991 Feb;101(2):109–113. doi: 10.1288/00005537-199102000-00001. [DOI] [PubMed] [Google Scholar]
  24. Melki J., Sheth P., Abdelhak S., Burlet P., Bachelot M. F., Lathrop M. G., Frezal J., Munnich A. Mapping of acute (type I) spinal muscular atrophy to chromosome 5q12-q14. The French Spinal Muscular Atrophy Investigators. Lancet. 1990 Aug 4;336(8710):271–273. doi: 10.1016/0140-6736(90)91803-i. [DOI] [PubMed] [Google Scholar]
  25. Miyamoto R. T., Campbell R. L., Fritsch M., Lochmueller G. Preservation of hearing in neurofibromatosis 2. Otolaryngol Head Neck Surg. 1990 Oct;103(4):619–624. doi: 10.1177/019459989010300416. [DOI] [PubMed] [Google Scholar]
  26. Narod S. A., Feunteun J., Lynch H. T., Watson P., Conway T., Lynch J., Lenoir G. M. Familial breast-ovarian cancer locus on chromosome 17q12-q23. Lancet. 1991 Jul 13;338(8759):82–83. doi: 10.1016/0140-6736(91)90076-2. [DOI] [PubMed] [Google Scholar]
  27. Parry D. M., Kaiser-Kupfer M. I., Sherman J. L., Pikus A., Eldridge R. Neurofibromatosis 2 (bilateral acoustic or central neurofibromatosis), a treatable cause of deafness. Recommendations for screening and follow-up based on study of one large kindred. Ann N Y Acad Sci. 1991;630:305–307. doi: 10.1111/j.1749-6632.1991.tb19615.x. [DOI] [PubMed] [Google Scholar]
  28. Pearson-Webb M. A., Kaiser-Kupfer M. I., Eldridge R. Eye findings in bilateral acoustic (central) neurofibromatosis: association with presenile lens opacities and cataracts but absence of Lisch nodules. N Engl J Med. 1986 Dec 11;315(24):1553–1554. doi: 10.1056/NEJM198612113152419. [DOI] [PubMed] [Google Scholar]
  29. Romeo G., Devoto M., Costa G., Roncuzzi L., Catizone L., Zucchelli P., Germino G. G., Keith T., Weatherall D. J., Reeders S. T. A second genetic locus for autosomal dominant polycystic kidney disease. Lancet. 1988 Jul 2;2(8601):8–11. doi: 10.1016/s0140-6736(88)92943-1. [DOI] [PubMed] [Google Scholar]
  30. Rouleau G. A., Haines J. L., Bazanowski A., Colella-Crowley A., Trofatter J. A., Wexler N. S., Conneally P. M., Gusella J. F. A genetic linkage map of the long arm of human chromosome 22. Genomics. 1989 Jan;4(1):1–6. doi: 10.1016/0888-7543(89)90306-6. [DOI] [PubMed] [Google Scholar]
  31. Rouleau G. A., Wertelecki W., Haines J. L., Hobbs W. J., Trofatter J. A., Seizinger B. R., Martuza R. L., Superneau D. W., Conneally P. M., Gusella J. F. Genetic linkage of bilateral acoustic neurofibromatosis to a DNA marker on chromosome 22. Nature. 1987 Sep 17;329(6136):246–248. doi: 10.1038/329246a0. [DOI] [PubMed] [Google Scholar]
  32. Sampson J. R., Yates J. R., Pirrit L. A., Fleury P., Winship I., Beighton P., Connor J. M. Evidence for genetic heterogeneity in tuberous sclerosis. J Med Genet. 1989 Aug;26(8):511–516. doi: 10.1136/jmg.26.8.511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Seizinger B. R., Rouleau G. A., Ozelius L. J., Lane A. H., Faryniarz A. G., Chao M. V., Huson S., Korf B. R., Parry D. M., Pericak-Vance M. A. Genetic linkage of von Recklinghausen neurofibromatosis to the nerve growth factor receptor gene. Cell. 1987 Jun 5;49(5):589–594. doi: 10.1016/0092-8674(87)90534-4. [DOI] [PubMed] [Google Scholar]
  34. Sobol H., Narod S. A., Nakamura Y., Boneu A., Calmettes C., Chadenas D., Charpentier G., Chatal J. F., Delepine N., Delisle M. J. Screening for multiple endocrine neoplasia type 2a with DNA-polymorphism analysis. N Engl J Med. 1989 Oct 12;321(15):996–1001. doi: 10.1056/NEJM198910123211502. [DOI] [PubMed] [Google Scholar]
  35. Tos M., Thomsen J. Epidemiology of acoustic neuromas. J Laryngol Otol. 1984 Jul;98(7):685–692. doi: 10.1017/s0022215100147292. [DOI] [PubMed] [Google Scholar]
  36. Ward K., O'Connell P., Carey J. C., Leppert M., Jolley S., Plaetke R., Ogden B., White R. Diagnosis of neurofibromatosis I by using tightly linked, flanking DNA markers. Am J Hum Genet. 1990 May;46(5):943–949. [PMC free article] [PubMed] [Google Scholar]
  37. Wertelecki W., Rouleau G. A., Superneau D. W., Forehand L. W., Williams J. P., Haines J. L., Gusella J. F. Neurofibromatosis 2: clinical and DNA linkage studies of a large kindred. N Engl J Med. 1988 Aug 4;319(5):278–283. doi: 10.1056/NEJM198808043190505. [DOI] [PubMed] [Google Scholar]
  38. Xu G. F., Nelson L., O'Connell P., White R. An Alu polymorphism intragenic to the neurofibromatosis type 1 gene (NF1). Nucleic Acids Res. 1991 Jul 11;19(13):3764–3764. doi: 10.1093/nar/19.13.3764. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Yandell D. W., Campbell T. A., Dayton S. H., Petersen R., Walton D., Little J. B., McConkie-Rosell A., Buckley E. G., Dryja T. P. Oncogenic point mutations in the human retinoblastoma gene: their application to genetic counseling. N Engl J Med. 1989 Dec 21;321(25):1689–1695. doi: 10.1056/NEJM198912213212501. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES