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. 1995;93:445–472.

Neurofibromatosis type 1 in children.

G R Beauchamp
PMCID: PMC1312070  PMID: 8719691

Abstract

OBJECTIVE: To document ophthalmic and general characteristics of Neurofibromatosis Type 1 (NF1) in children; and to characterize the iris changes of NF1 including their variability and reliability. DESIGN AND PATIENTS: One hundred and ninety-six patients with NF1 were evaluated for general characteristics; 156 patients underwent prospective eye evaluations; and 151 NF1 patients and controls had iris photography in accordance with a protocol. Masked evaluation of photographs compared to a known diagnosis, and interobserver reliability tests were performed. MAIN OUTCOME MEASURES: Incidence of iris changes consistent with NF1 (Lisch nodules, plus) by age group; spectrum of iris changes found; correlation of iris findings to known diagnosis and Kappa coefficients for interobserver reliability. RESULTS: Iris changes were common in children over age 5, and increased with age; masked evaluation of photographs compared to a known diagnosis yielded fair to poor correlation (Kappa = -.02 to .50); interobserver reliability was poor (Kappa = -.02 to .24, overall .174); iris changes found in NF1 are more diverse than classic descriptions of Lisch nodules, and including a broader spectrum probably increases the sensitivity and decreases the specificity of their diagnostic value. CONCLUSION: Iris changes as a diagnostic marker for NF1 may need rethinking; this study calls to question their reliability and validity.

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Selected References

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

  1. Allanson J. E., Hall J. G., Van Allen M. I. Noonan phenotype associated with neurofibromatosis. Am J Med Genet. 1985 Jul;21(3):457–462. doi: 10.1002/ajmg.1320210307. [DOI] [PubMed] [Google Scholar]
  2. Bader J. L., Miller R. W. Neurofibromatosis and childhood leukemia. J Pediatr. 1978 Jun;92(6):925–929. doi: 10.1016/s0022-3476(78)80362-x. [DOI] [PubMed] [Google Scholar]
  3. Bardelli A. M., Hadjistilianou T. Buphthalmos and progressive elephantiasis in neurofibromatosis. A report of three cases. Ophthalmic Paediatr Genet. 1989 Dec;10(4):279–286. doi: 10.3109/13816818909009883. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Bolande R. P. Neurofibromatosis--the quintessential neurocristopathy: pathogenetic concepts and relationships. Adv Neurol. 1981;29:67–75. [PubMed] [Google Scholar]
  6. Brockes J. P., Breakefield X. O., Martuza R. L. Glial growth factor-like activity in Schwann cell tumors. Ann Neurol. 1986 Sep;20(3):317–322. doi: 10.1002/ana.410200308. [DOI] [PubMed] [Google Scholar]
  7. CROWE F. W. AXILLARY FRECKLING AS A DIAGNOSTIC AID IN NEUROFIBROMATOSIS. Ann Intern Med. 1964 Dec;61:1142–1143. doi: 10.7326/0003-4819-61-6-1142. [DOI] [PubMed] [Google Scholar]
  8. CROWE F. W., SCHULL W. J. Diagnostic importance of café-au-lait spot in neurofibromatosis. AMA Arch Intern Med. 1953 Jun;91(6):758–766. doi: 10.1001/archinte.1953.00240180067008. [DOI] [PubMed] [Google Scholar]
  9. Castillo M., Quencer R. M., Glaser J., Altman N. Congenital glaucoma and buphthalmos in a child with neurofibromatosis. J Clin Neuroophthalmol. 1988 Mar;8(1):69–71. [PubMed] [Google Scholar]
  10. Cooper P. H., Frierson H. F., Kayne A. L., Sabio H. Association of juvenile xanthogranuloma with juvenile myeloid leukemia. Arch Dermatol. 1984 Mar;120(3):371–375. [PubMed] [Google Scholar]
  11. Crawford A. H., Jr, Bagamery N. Osseous manifestations of neurofibromatosis in childhood. J Pediatr Orthop. 1986 Jan-Feb;6(1):72–88. doi: 10.1097/01241398-198601000-00015. [DOI] [PubMed] [Google Scholar]
  12. Destro M., D'Amico D. J., Gragoudas E. S., Brockhurst R. J., Pinnolis M. K., Albert D. M., Topping T. M., Puliafito C. A. Retinal manifestations of neurofibromatosis. Diagnosis and management. Arch Ophthalmol. 1991 May;109(5):662–666. doi: 10.1001/archopht.1991.01080050076033. [DOI] [PubMed] [Google Scholar]
  13. Eldridge R., Denckla M. B., Bien E., Myers S., Kaiser-Kupfer M. I., Pikus A., Schlesinger S. L., Parry D. M., Dambrosia J. M., Zasloff M. A. Neurofibromatosis type 1 (Recklinghausen's disease). Neurologic and cognitive assessment with sibling controls. Am J Dis Child. 1989 Jul;143(7):833–837. [PubMed] [Google Scholar]
  14. Eliason M. J. Neurofibromatosis: implications for learning and behavior. J Dev Behav Pediatr. 1986 Jun;7(3):175–179. [PubMed] [Google Scholar]
  15. Flüeler U., Boltshauser E., Kilchhofer A. Iris hamartomata as diagnostic criterion in neurofibromatosis. Neuropediatrics. 1986 Nov;17(4):183–185. doi: 10.1055/s-2008-1052525. [DOI] [PubMed] [Google Scholar]
  16. Goldgar D. E., Green P., Parry D. M., Mulvihill J. J. Multipoint linkage analysis in neurofibromatosis type I: an international collaboration. Am J Hum Genet. 1989 Jan;44(1):6–12. [PMC free article] [PubMed] [Google Scholar]
  17. Grant W. M., Walton D. S. Distinctive gonioscopic findings in glaucoma due to neurofibromatosis. Arch Ophthalmol. 1968 Feb;79(2):127–134. doi: 10.1001/archopht.1968.03850040129003. [DOI] [PubMed] [Google Scholar]
  18. Hall B. D. Congenital lid ptosis associated with neurofibromatosis. Am J Med Genet. 1986 Nov;25(3):595–597. doi: 10.1002/ajmg.1320250323. [DOI] [PubMed] [Google Scholar]
  19. Harkin J. C. Pathology of nerve sheath tumors. Ann N Y Acad Sci. 1986;486:147–154. doi: 10.1111/j.1749-6632.1986.tb48070.x. [DOI] [PubMed] [Google Scholar]
  20. Huson S., Jones D., Beck L. Ophthalmic manifestations of neurofibromatosis. Br J Ophthalmol. 1987 Mar;71(3):235–238. doi: 10.1136/bjo.71.3.235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kaye L. D., Rothner A. D., Beauchamp G. R., Meyers S. M., Estes M. L. Ocular findings associated with neurofibromatosis type II. Ophthalmology. 1992 Sep;99(9):1424–1429. doi: 10.1016/s0161-6420(92)31789-0. [DOI] [PubMed] [Google Scholar]
  22. Le Douarin N. M. Investigations on the neural crest. Methodological aspects and recent advances. Ann N Y Acad Sci. 1986;486:66–86. doi: 10.1111/j.1749-6632.1986.tb48063.x. [DOI] [PubMed] [Google Scholar]
  23. Lewis R. A., Riccardi V. M. Von Recklinghausen neurofibromatosis. Incidence of iris hamartomata. Ophthalmology. 1981 Apr;88(4):348–354. doi: 10.1016/s0161-6420(81)35034-9. [DOI] [PubMed] [Google Scholar]
  24. Liang J. C., Juarez C. P., Goldberg M. F. Bilateral bicolored irides with Hirschsprung's disease. A neural crest syndrome. Arch Ophthalmol. 1983 Jan;101(1):69–73. doi: 10.1001/archopht.1983.01040010071011. [DOI] [PubMed] [Google Scholar]
  25. Listernick R., Charrow J., Greenwald M. J., Esterly N. B. Optic gliomas in children with neurofibromatosis type 1. J Pediatr. 1989 May;114(5):788–792. doi: 10.1016/s0022-3476(89)80137-4. [DOI] [PubMed] [Google Scholar]
  26. Listernick R., Charrow J. Neurofibromatosis type 1 in childhood. J Pediatr. 1990 Jun;116(6):845–853. doi: 10.1016/s0022-3476(05)80639-0. [DOI] [PubMed] [Google Scholar]
  27. Lubs M. L., Bauer M. S., Formas M. E., Djokic B. Lisch nodules in neurofibromatosis type 1. N Engl J Med. 1991 May 2;324(18):1264–1266. doi: 10.1056/NEJM199105023241807. [DOI] [PubMed] [Google Scholar]
  28. McKeen E. A., Bodurtha J., Meadows A. T., Douglass E. C., Mulvihill J. J. Rhabdomyosarcoma complicating multiple neurofibromatosis. J Pediatr. 1978 Dec;93(6):992–993. doi: 10.1016/s0022-3476(78)81233-5. [DOI] [PubMed] [Google Scholar]
  29. Meinecke P. Evidence that the "neurofibromatosis-Noonan syndrome" is a variant of von Recklinghausen neurofibromatosis. Am J Med Genet. 1987 Mar;26(3):741–745. doi: 10.1002/ajmg.1320260331. [DOI] [PubMed] [Google Scholar]
  30. Mendez H. M. The neurofibromatosis-Noonan syndrome. Am J Med Genet. 1985 Jul;21(3):471–476. doi: 10.1002/ajmg.1320210309. [DOI] [PubMed] [Google Scholar]
  31. Menon A. G., Anderson K. M., Riccardi V. M., Chung R. Y., Whaley J. M., Yandell D. W., Farmer G. E., Freiman R. N., Lee J. K., Li F. P. Chromosome 17p deletions and p53 gene mutations associated with the formation of malignant neurofibrosarcomas in von Recklinghausen neurofibromatosis. Proc Natl Acad Sci U S A. 1990 Jul;87(14):5435–5439. doi: 10.1073/pnas.87.14.5435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Mulvihill J. J., Parry D. M., Sherman J. L., Pikus A., Kaiser-Kupfer M. I., Eldridge R. NIH conference. Neurofibromatosis 1 (Recklinghausen disease) and neurofibromatosis 2 (bilateral acoustic neurofibromatosis). An update. Ann Intern Med. 1990 Jul 1;113(1):39–52. doi: 10.7326/0003-4819-113-1-39. [DOI] [PubMed] [Google Scholar]
  33. Norman M. E. Neurofibromatosis in a family. Am J Dis Child. 1972 Feb;123(2):159–160. doi: 10.1001/archpedi.1972.02110080137019. [DOI] [PubMed] [Google Scholar]
  34. Obringer A. C., Meadows A. T., Zackai E. H. The diagnosis of neurofibromatosis-1 in the child under the age of 6 years. Am J Dis Child. 1989 Jun;143(6):717–719. doi: 10.1001/archpedi.1989.02150180099028. [DOI] [PubMed] [Google Scholar]
  35. Opitz J. M., Weaver D. D. The neurofibromatosis-Noonan syndrome. Am J Med Genet. 1985 Jul;21(3):477–490. doi: 10.1002/ajmg.1320210310. [DOI] [PubMed] [Google Scholar]
  36. Petersen J. M., Ferguson D. R. Gastrointestinal neurofibromatosis. J Clin Gastroenterol. 1984 Dec;6(6):529–534. doi: 10.1097/00004836-198412000-00008. [DOI] [PubMed] [Google Scholar]
  37. Ragge N. K., Falk R. E., Cohen W. E., Murphree A. L. Images of Lisch nodules across the spectrum. Eye (Lond) 1993;7(Pt 1):95–101. doi: 10.1038/eye.1993.20. [DOI] [PubMed] [Google Scholar]
  38. Riccardi V. M., Dobson C. E., 2nd, Chakraborty R., Bontke C. The pathophysiology of neurofibromatosis: IX. Paternal age as a factor in the origin of new mutations. Am J Med Genet. 1984 May;18(1):169–176. doi: 10.1002/ajmg.1320180121. [DOI] [PubMed] [Google Scholar]
  39. Riccardi V. M. Mast-cell stabilization to decrease neurofibroma growth. Preliminary experience with ketotifen. Arch Dermatol. 1987 Aug;123(8):1011–1016. [PubMed] [Google Scholar]
  40. Riccardi V. M. Neurofibromatosis: clinical heterogeneity. Curr Probl Cancer. 1982 Aug;7(2):1–34. doi: 10.1016/s0147-0272(82)80016-0. [DOI] [PubMed] [Google Scholar]
  41. Riccardi V. M. Neurofibromatosis: past, present, and future. N Engl J Med. 1991 May 2;324(18):1283–1285. doi: 10.1056/NEJM199105023241812. [DOI] [PubMed] [Google Scholar]
  42. Riccardi V. M. Pathophysiology of neurofibromatosis. IV. Dermatologic insights into heterogeneity and pathogenesis. J Am Acad Dermatol. 1980 Aug;3(2):157–166. [PubMed] [Google Scholar]
  43. Riccardi V. M. Von Recklinghausen neurofibromatosis. N Engl J Med. 1981 Dec 31;305(27):1617–1627. doi: 10.1056/NEJM198112313052704. [DOI] [PubMed] [Google Scholar]
  44. Riccardi V. M., Wald J. S. Discounting an adverse maternal effect on severity of neurofibromatosis. Pediatrics. 1987 Mar;79(3):386–393. [PubMed] [Google Scholar]
  45. Riopelle R. J., Riccardi V. M., Faulkner S., Martin M. C. Serum neuronal growth factor levels in von Recklinghausen's neurofibromatosis. Ann Neurol. 1984 Jul;16(1):54–59. doi: 10.1002/ana.410160111. [DOI] [PubMed] [Google Scholar]
  46. Rosman N. P., Pearce J. The brain in multiple neurofibromatosis (von Recklinghausen's disease): a suggested neuropathological basis for the associated mental defect. Brain. 1967 Dec;90(4):829–838. doi: 10.1093/brain/90.4.829. [DOI] [PubMed] [Google Scholar]
  47. Samuelsson B., Axelsson R. Neurofibromatosis. A clinical and genetic study of 96 cases in Gothenburg, Sweden. Acta Derm Venereol Suppl (Stockh) 1981;95:67–71. [PubMed] [Google Scholar]
  48. Satran L., Letson R. D., Seljeskog E. L. Neurofibromatosis with congenital glaucoma and buphthalmos in a newborn. Am J Dis Child. 1980 Feb;134(2):182–183. doi: 10.1001/archpedi.1980.02130140056016. [DOI] [PubMed] [Google Scholar]
  49. Savino P. J., Glaser J. S., Luxenberg M. N. Pulsating enophthalmos and choroidal hamartomas: two rare stigmata of neurofibromatosis. Br J Ophthalmol. 1977 Jul;61(7):483–488. doi: 10.1136/bjo.61.7.483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Saxena K. M. Endocrine manifestations of neurofibromatosis in children. Am J Dis Child. 1970 Sep;120(3):265–271. doi: 10.1001/archpedi.1970.02100080149020. [DOI] [PubMed] [Google Scholar]
  51. Schenkein I., Bueker E. D., Helson L., Axelrod F., Dancis J. Increased nerve-growth-stimulating activity in disseminated neurofibromatosis. N Engl J Med. 1974 Mar 14;290(11):613–614. doi: 10.1056/NEJM197403142901108. [DOI] [PubMed] [Google Scholar]
  52. 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]
  53. Sonnenfeld K. H., Bernd P., Sobue G., Lebwohl M., Rubenstein A. E. Nerve growth factor receptors on dissociated neurofibroma Schwann-like cells. Cancer Res. 1986 Mar;46(3):1446–1452. [PubMed] [Google Scholar]
  54. Stay E. J., Vawter G. The relationship between nephroblastoma and neurofibromatosis (Von Recklinghausen's disease). Cancer. 1977 Jun;39(6):2550–2555. doi: 10.1002/1097-0142(197706)39:6<2550::aid-cncr2820390636>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
  55. Sørensen S. A., Mulvihill J. J., Nielsen A. Long-term follow-up of von Recklinghausen neurofibromatosis. Survival and malignant neoplasms. N Engl J Med. 1986 Apr 17;314(16):1010–1015. doi: 10.1056/NEJM198604173141603. [DOI] [PubMed] [Google Scholar]
  56. Taniuchi M., Clark H. B., Johnson E. M., Jr Induction of nerve growth factor receptor in Schwann cells after axotomy. Proc Natl Acad Sci U S A. 1986 Jun;83(11):4094–4098. doi: 10.1073/pnas.83.11.4094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Thompson J. A. Diagnosis and treatment of headache in the pediatric patient. Curr Probl Pediatr. 1980 Aug;10(10):1–52. doi: 10.1016/s0045-9380(80)80008-9. [DOI] [PubMed] [Google Scholar]
  58. Toonstra J., Dandrieu M. R., Ippel P. F., Delleman J. W., Rupert P. H., Jr, Huitema H. B. Are Lisch nodules an ocular marker of the neurofibromatosis gene in otherwise unaffected family members? Dermatologica. 1987;174(5):232–235. doi: 10.1159/000249186. [DOI] [PubMed] [Google Scholar]
  59. Varnhagen C. K., Lewin S., Das J. P., Bowen P., Ma K., Klimek M. Neurofibromatosis and psychological processes. J Dev Behav Pediatr. 1988 Oct;9(5):257–265. [PubMed] [Google Scholar]
  60. Wallace M. R., Marchuk D. A., Andersen L. B., Letcher R., Odeh H. M., Saulino A. M., Fountain J. W., Brereton A., Nicholson J., Mitchell A. L. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science. 1990 Jul 13;249(4965):181–186. doi: 10.1126/science.2134734. [DOI] [PubMed] [Google Scholar]
  61. Weichert K. A., Dine M. S., Benton C., Silverman F. N. Macrocranium and neurofibromatosis. Radiology. 1973 Apr;107(1):163–166. doi: 10.1148/107.1.163. [DOI] [PubMed] [Google Scholar]
  62. Weston J. A. The regulation of normal and abnormal neural crest cell development. Adv Neurol. 1981;29:77–95. [PubMed] [Google Scholar]
  63. Williamson T. H., Garner A., Moore A. T. Structure of Lisch nodules in neurofibromatosis type 1. Ophthalmic Paediatr Genet. 1991 Mar;12(1):11–17. doi: 10.3109/13816819109023079. [DOI] [PubMed] [Google Scholar]
  64. Xu G. F., O'Connell P., Viskochil D., Cawthon R., Robertson M., Culver M., Dunn D., Stevens J., Gesteland R., White R. The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell. 1990 Aug 10;62(3):599–608. doi: 10.1016/0092-8674(90)90024-9. [DOI] [PubMed] [Google Scholar]
  65. Yankner B. A., Shooter E. M. The biology and mechanism of action of nerve growth factor. Annu Rev Biochem. 1982;51:845–868. doi: 10.1146/annurev.bi.51.070182.004213. [DOI] [PubMed] [Google Scholar]
  66. Zehavi C., Romano A., Goodman R. M. Iris (Lisch) nodules in neurofibromatosis. Clin Genet. 1986 Jan;29(1):51–55. doi: 10.1111/j.1399-0004.1986.tb00770.x. [DOI] [PubMed] [Google Scholar]
  67. Zelkowitz M. Neurofibromatosis fibroblasts: abnormal growth and binding to epidermal growth factor. Adv Neurol. 1981;29:173–189. [PubMed] [Google Scholar]

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