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July 2, 1997, Vol 278, No. 1 >
ARTICLE | July 2, 1997

The Diagnostic Evaluation and Multidisciplinary Management of Neurofibromatosis 1 and Neurofibromatosis 2 FREE

David H. Gutmann, MD, PhD; Arthur Aylsworth, MD; John C. Carey, MD; Bruce Korf, MD, PhD; Joan Marks, PhD; Reed E. Pyeritz, MD, PhD; Allan Rubenstein, MD; David Viskochil, MD, PhD
[+] Author Affiliations

The authors comprise the National Neurofibromatosis Foundation Clinical Care Advisory Board.

Reprints: David H. Gutmann, MD, PhD, Neurofibromatosis Program, St Louis Children's Hospital, Department of Neurology, Washington University School of Medicine, 660 S Euclid Ave, Box 8111, St Louis, MO 63110 (e-mail: gutmannd@neuro.wustl.edu).


JAMA. 1997;278(1):51-57. doi:10.1001/jama.1997.03550010065042
Text Size: A A A
Published online
Article
References

Objective.  —Neurofibromatosis 1 and neurofibromatosis 2 are autosomal dominant genetic disorders in which affected individuals develop both benign and malignant tumors at an increased frequency. Since the original National Institutes of Health Consensus Development Conference in 1987, there has been significant progress toward a more complete understanding of the molecular bases for neurofibromatosis 1 and neurofibromatosis 2. Our objective was to determine the diagnostic criteria for neurofibromatosis 1 and neurofibromatosis 2, recommendations for the care of patients and their families at diagnosis and during routine follow-up, and the role of DNA diagnostic testing in the evaluation of these disorders.

Data Sources.  —Published reports from 1966 through 1996 obtained by MEDLINE search and studies presented at national and international meetings.

Study Selection.  —All studies were reviewed and analyzed by consensus from multiple authors.

Data Extraction.  —Peer-reviewed published data were critically evaluated by independent extraction by multiple authors.

Data Synthesis.  —The main results of the review were qualitative and were reviewed by neurofibromatosis clinical directors worldwide through an Internet Web site.

Conclusions.  —On the basis of the information presented in this review, we propose a comprehensive approach to the diagnosis and treatment of individuals with neurofibromatosis 1 and neurofibromatosis 2.

REFERENCES

1 +
Riccardi VM.  Neurofibromatosis: past, present, and future . N Engl J Med . 1991;;324:1283-1285.
2 +
Riccardi VM, Eichner JE. Neurofibromatosis: Phenotype, Natural History and Pathogenesis . 2nd ed. Baltimore, Md: Johns Hopkins University Press; 1992;.
3 +
Huson SM, Hughes RAC. The Neurofibromatoses: A Pathogenetic and Clinical Overview . London, United Kingdom: Chapman & Hall; 1994;.
4 +
Bader JL.  Neurofibromatosis and cancer . Ann N Y Acad Sci . 1986;;486:57-65.
5 +
National Institutes of Health Consensus Development Conference.  Neurofibromatosis: Conference Statement . Arch Neurol . 1988;;45:575-578.
6 +
Mulvihill JJ, Parry DM, Sherman JL, Pikus A, Kaiser-Kupfer MI, Eldridge R.  Neurofibromatosis 1 (Recklinghausen disease) and neurofibromatosis 2 (bilateral acoustic neurofibromatosis): an update . Ann Intern Med . 1990;;113:39-52.
7 +
Wallace MR, Marchuk DA, Andersen LB, et al.  Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients . Science . 1990;;249:181-186.
8 +
Cawthon RM, Weiss M, Xu G, et al.  A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations . Cell . 1990;;62:193-201.
9 +
Viskochil D, Buchberg AM, Xu G, et al.  Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus . Cell . 1990;;62:187-192.
10 +
Rouleau GA, Merel P, Lutchman M, et al.  Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2 . Nature . 1993;;363:515-521.
11 +
Trofatter JA, MacCollin MM, Rutter JL, et al.  A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor . Cell . 1993;;72:1-20.
12 +
Korf BR.  Diagnostic outcome in children with multiple cafe-au-lait spots . Pediatrics . 1992;;90:924-927.
13 +
Crowe FW.  Axillary freckling as a diagnostic aid in neurofibromatosis . Ann Intern Med . 1964;;61:1142-1143.
14 +
Obringer AC, Meadows AT, Zackai EH.  The diagnosis of neurofibromatosis 1 in the child under the age of 6 years . Am J Dis Child . 1989;;143:717-719.
15 +
Huson SM, Harper PS, Compston DAS.  Von Recklinghausen neurofibromatosis: a clinical and population study in South East Wales . Brain . 1988;;111:1355-1381.
16 +
Duffner PK, Cohen ME, Seidel FG, Shucard DW.  The significance of MRI abnormalities in children with neurofibromatosis . Neurology . 1989;;39:373-378.
17 +
North K.  Neurofibromatosis type 1: review of the first 200 patients in an Australian clinic . J Child Neurol . 1993;;8:395-402.
18 +
North K, Joy P, Yuille D, et al.  Specific learning disability in children with neurofibromatosis type 1: significance of MRI abnormalities . Neurology . 1994;;44:878-883.
19 +
Moore BD, Slopis JM, Schomer D, Jackson EF, Levy BM.  Neuropsychological significance of areas of high signal intensity on brain MRIs of children with neurofibromatosis . Neurology . 1996;;46:1660-1668.
20 +
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;;195:721-724.
21 +
Matsui I, Tanimura M, Kobayashi N, Sawada T, Nagahara N, Akatsuka J-I.  Neurofibromatosis type 1 and cancer . Cancer . 1993;;72:746-754.
22 +
Woodruff JM, Marshall ML, Godwin TA, Funkhouser JW, Thompson JW, Erlandson RA.  Plexiform (multinodular) schwannoma: a tumor simulating the plexiform neurofibroma . Am J Surg Pathol . 1983;;7:691-697.
23 +
Zvulunov A, Barak Y, Metzker A.  Juvenile xanthogranuloma, neurofibromatosis, and juvenile chronic myelogenous leukemia: world statistical analysis . Arch Dermatol . 1995;;131:904-908.
24 +
Gutmann DH, Gurney JG, Shannon KM.  Juvenile xanthogranuloma, neurofibromatosis 1 and juvenile chronic myeloid leukemia . Arch Dermatol . 1996;;132:1390-1391.
25 +
Listernick R, Darling C, Greenwald M, Strauss L, Charrow J.  Optic pathway tumors in children: the effect of neurofibromatosis 1 on clinical manifestations and natural history . J Pediatr . 1995;;127:718-722.
26 +
Listernick R, Louis DN, Packer RJ, Gutmann DH.  Optic pathway glioma in children with neurofibromatosis 1: consensus statement from the Optic Pathway Glioma Task Force . Ann Neurol . 1997;;41:143-149.
27 +
Packer RJ, Lange B, Ater J, et al.  Carboplatinum and vincristine for recurrent and newly diagnosed low-grade gliomas of childhood . J Clin Oncol . 1993;;11:850-856.
28 +
Hofman KJ, Harris EL, Bryan N, Denckla M.  Neurofibromatosis type 1: the cognitive phenotype . J Pediatr . 1994;;124:S1-S8.
29 +
Chapman CA, Waber DP, Bassett N, Urion DK, Korf BR.  Neurobehavioral profiles of children with neurofibromatosis 1 referred for learning disabilities are sex-specific . Am J Med Genet . 1996;;67:127-132.
30 +
Zigmond N.  Models for the delivery of special education services to students with learning disabilities in public school . J Child Neurol . 1995;;10:886-892.
31 +
Clementi M, Battistella PA, Rizzi L, Boni S, Tenconi R.  Headache in patients with neurofibromatosis type 1 . Headache . 1996;;36:10.
32 +
Evans DGR, Huson SM, Donnai D, et al.  A clinical study of type 2 neurofibromatosis . Q J Med . 1992;;304:603-618.
33 +
Evans DGR, Huson SM, Donnai D, et al.  A genetic study of type 2 neurofibromatosis in the United Kingdom, I: prevalence, mutation rate, fitness, and confirmation of maternal transmission effect on severity . J Med Genet . 1992;;29:841-846.
34 +
Parry DM, Eldridge R, Kaiser-Kupfer MI, Bouzas EA, Pikus A, Patronas N.  Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity . Am J Med Genet . 1994;;52:450-461.
35 +
Mautner V-F, Lindenau M, Baser ME, et al.  The neuroimaging and clinical spectrum of neurofibromatosis 2 . Neurosurgery . 1996;;38:880-886.
36 +
Ragge NK, Baser ME, Klein J, et al.  Ocular abnormalities in neurofibromatosis 2 . Am J Ophthalmol . 1995;;120:634-641.
37 +
Briggs RJS, Brackmann DE, Baser ME, Hitselberger WE.  Comprehensive management of bilateral acoustic neuromas . Arch Otolaryngol Head Neck Surg . 1994;;120:1307-1314.
38 +
Ojemann RG.  Management of acoustic neuromas (vestibular schwannomas) . Clin Neurosurg . 1993;;40:489-535.
39 +
Nadol J, Chiong C, Ojemann R, et al.  Preservation of hearing and facial nerve function in resection of acoustic neuroma . Laryngoscope . 1992;;102:1153-1158.
40 +
Miyamoto R, Campbell R, Fritsch M, Lochmueller G.  Preservation of hearing in neurofibromatosis 2 . Otolaryngol Head Neck Surg . 1990;;103:619-624.
41 +
Linskey M, Lunsford D, Flickinger J.  Tumor control after stereotactic radiosurgery in neurofibromatosis patients with bilateral acoustic tumors . Neurosurgery . 1992;;31:829-838.
42 +
Lunsford LD, Linskey M.  Stereotactic radiosurgery in the treatment of patients with acoustic tumors . Otolaryngol Clin North Am . 1992;;25:471-491.
43 +
Baser M, MacCollin M, Sujansky E, Evans DGR, Rubenstein A. Malignant nervous system tumors in patients with neurofibromatosis 2. Presented at the 1996 FASEB Summer Research Conference on Neurofibromatosis, Snowmass, Colo, June 29, 1996.
44 +
Kanter WR, Eldridge R, Fabricant R, Allen JC, Koerber T.  Central neurofibromatosis with bilateral acoustic neuroma: genetic, clinical and biochemical distinctions from peripheral neurofibromatosis . Neurology . 1980;;30:851-859.
45 +
Hoffman R, Kohan D, Cohen N.  Cochlear implants in the management of bilateral acoustic neuromas . Am J Otol . 1992;;13:525-528.
46 +
Kayes LM, Riccardi VM, Burke W, Bennett RL, Stephens K.  Large de novo DNA deletion in a patient with sporadic neurofibromatosis, mental retardation and dysmorphism . J Med Genet . 1992;;29:686-690.
47 +
Wu BL, Austin MA, Schneider GH, Boles RG, Korf BR.  Deletion of the entire NF1 gene detected by FISH: four deletion patients associated with severe manifestations . Am J Med Genet . 1995;;59:528-535.
48 +
Ruttledge MH, Andermann AA, Phelan CM, et al.  Type of mutation in the neurofibromatosis type 2 gene (NF2) frequently determines severity of disease . Am J Hum Genet . 1996;;59:331-342.
49 +
Parry DM, MacCollin MM, Kaiser-Kupfer MI, et al.  Germ-line mutations in the neurofibromatosis 2 gene: correlations with disease severity and retinal abnormalities . Am J Hum Genetgroup . 1996;;59:529-539.
50 +
Scoles DR, Baser ME, Pulst S-M.  A missense mutation in the neurofibromatosis 2 gene occurs in patients with mild and severe phenotypes . Neurology . 1996;;47:544-546.
51 +
Arnsmeier SL, Riccardi VM, Paller AS.  Familial multiple cafe-au-lait spots . Arch Dermatol . 1994;;130:1425-1426.
52 +
Charrow J, Listernick R, Ward K.  Autosomal dominant multiple cafe-au-lait spots and neurofibromatosis-1: evidence of non-linkage . Am J Med Genet . 1993;;45:606-608.
53 +
Abelovich D, Gelman-Kohan Z, Silverstein S, et al.  Familial cafe au lait spots: a variant of neurofibromatosis type 1 . J Med Genet . 1995;;32:985-986.
54 +
Sharland M, Burch M, McKenna WM, Paton MA.  A clinical study of Noonan syndrome . Arch Dis Child . 1992;;67:178-183.
55 +
Watson GH.  Pulmonary stenosis, cafe-au-lait spots, and dull intelligence . Arch Dis Child . 1967;;42:303-307.
56 +
Edman Ahlbom B, Dahl N, Zetterqvist P, Anneren G.  Noonan syndrome with cafe-au-lait spots and multiple lentigines syndrome are not linked to-the neurofibromatosis type 1 locus . Clin Genet . 1995;;48:85-89.
57 +
Allanson JE, Upadhyaya M, Watson GH, et al.  Watson syndrome: is it a subtype of type 1 neurofibromatosis? J Med Genet . 1991;;28:752-756.
58 +
MacCollin M, Woodfin W, Kronn D, Short MP.  Schwannomatosis: a clinical and pathologic study . Neurology . 1996;;46:1072-1079.
59 +
Pulst SM, Rouleau GA, Marineau C, Fain P, Sieb JP.  Familial meningioma is not allelic to neurofibromatosis 2 . Neurology . 1993;;43:2096-2098.
60 +
Moss C, Green SH.  What is segmental neurofibromatosis? Br J Dermatol . 1994;;130:106-110.
61 +
Colman SD, Rasmussen SA, Ho VT, Abernathy CR, Wallace MR.  Somatic mosaicism in a patient with neurofibromatosis type 1 . Am J Hum Genet . 1996;;58:484-490.
62 +
Sloan JB, Fretzin DF, Bovenmyer DA.  Genetic counseling in segmental neurofibromatosis . J Am Acad Dermatol . 1990;;22:461-467.
63 +
Heim RA, Silverman LM, Farber RA, KamMorgan LNW, Luce MC.  Screening for truncated NF1 proteins . Nat Genet . 1994;;8:218-219.
64 +
Evans DGR, Bourn D, Wallace A, Ramsden RT, Mitchell JD, Strachan T.  Diagnostic issues in a family with late onset type 2 neurofibromatosis . J Med Genet . 1995;;32:470-474.
65 +
Bourn D, Carter SA, Mason S, Gareth D, Evans R, Strachan T.  Germline mutations in the neurofibromatosis type 2 tumour suppressor gene . Hum Mol Genet . 1994;;3:813-816.
66 +
Merel P, Khe HX, Sanson M, et al.  Screening for germline mutations in the neurofibromatosis 2 gene . Genes Chromosomes Cancer . 1995;;12:117-121.

Figures

Tables

Interactive Graphics

Video

Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Riccardi VM.  Neurofibromatosis: past, present, and future . N Engl J Med . 1991;;324:1283-1285.
2 +
Riccardi VM, Eichner JE. Neurofibromatosis: Phenotype, Natural History and Pathogenesis . 2nd ed. Baltimore, Md: Johns Hopkins University Press; 1992;.
3 +
Huson SM, Hughes RAC. The Neurofibromatoses: A Pathogenetic and Clinical Overview . London, United Kingdom: Chapman & Hall; 1994;.
4 +
Bader JL.  Neurofibromatosis and cancer . Ann N Y Acad Sci . 1986;;486:57-65.
5 +
National Institutes of Health Consensus Development Conference.  Neurofibromatosis: Conference Statement . Arch Neurol . 1988;;45:575-578.
6 +
Mulvihill JJ, Parry DM, Sherman JL, Pikus A, Kaiser-Kupfer MI, Eldridge R.  Neurofibromatosis 1 (Recklinghausen disease) and neurofibromatosis 2 (bilateral acoustic neurofibromatosis): an update . Ann Intern Med . 1990;;113:39-52.
7 +
Wallace MR, Marchuk DA, Andersen LB, et al.  Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients . Science . 1990;;249:181-186.
8 +
Cawthon RM, Weiss M, Xu G, et al.  A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations . Cell . 1990;;62:193-201.
9 +
Viskochil D, Buchberg AM, Xu G, et al.  Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus . Cell . 1990;;62:187-192.
10 +
Rouleau GA, Merel P, Lutchman M, et al.  Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2 . Nature . 1993;;363:515-521.
11 +
Trofatter JA, MacCollin MM, Rutter JL, et al.  A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor . Cell . 1993;;72:1-20.
12 +
Korf BR.  Diagnostic outcome in children with multiple cafe-au-lait spots . Pediatrics . 1992;;90:924-927.
13 +
Crowe FW.  Axillary freckling as a diagnostic aid in neurofibromatosis . Ann Intern Med . 1964;;61:1142-1143.
14 +
Obringer AC, Meadows AT, Zackai EH.  The diagnosis of neurofibromatosis 1 in the child under the age of 6 years . Am J Dis Child . 1989;;143:717-719.
15 +
Huson SM, Harper PS, Compston DAS.  Von Recklinghausen neurofibromatosis: a clinical and population study in South East Wales . Brain . 1988;;111:1355-1381.
16 +
Duffner PK, Cohen ME, Seidel FG, Shucard DW.  The significance of MRI abnormalities in children with neurofibromatosis . Neurology . 1989;;39:373-378.
17 +
North K.  Neurofibromatosis type 1: review of the first 200 patients in an Australian clinic . J Child Neurol . 1993;;8:395-402.
18 +
North K, Joy P, Yuille D, et al.  Specific learning disability in children with neurofibromatosis type 1: significance of MRI abnormalities . Neurology . 1994;;44:878-883.
19 +
Moore BD, Slopis JM, Schomer D, Jackson EF, Levy BM.  Neuropsychological significance of areas of high signal intensity on brain MRIs of children with neurofibromatosis . Neurology . 1996;;46:1660-1668.
20 +
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;;195:721-724.
21 +
Matsui I, Tanimura M, Kobayashi N, Sawada T, Nagahara N, Akatsuka J-I.  Neurofibromatosis type 1 and cancer . Cancer . 1993;;72:746-754.
22 +
Woodruff JM, Marshall ML, Godwin TA, Funkhouser JW, Thompson JW, Erlandson RA.  Plexiform (multinodular) schwannoma: a tumor simulating the plexiform neurofibroma . Am J Surg Pathol . 1983;;7:691-697.
23 +
Zvulunov A, Barak Y, Metzker A.  Juvenile xanthogranuloma, neurofibromatosis, and juvenile chronic myelogenous leukemia: world statistical analysis . Arch Dermatol . 1995;;131:904-908.
24 +
Gutmann DH, Gurney JG, Shannon KM.  Juvenile xanthogranuloma, neurofibromatosis 1 and juvenile chronic myeloid leukemia . Arch Dermatol . 1996;;132:1390-1391.
25 +
Listernick R, Darling C, Greenwald M, Strauss L, Charrow J.  Optic pathway tumors in children: the effect of neurofibromatosis 1 on clinical manifestations and natural history . J Pediatr . 1995;;127:718-722.
26 +
Listernick R, Louis DN, Packer RJ, Gutmann DH.  Optic pathway glioma in children with neurofibromatosis 1: consensus statement from the Optic Pathway Glioma Task Force . Ann Neurol . 1997;;41:143-149.
27 +
Packer RJ, Lange B, Ater J, et al.  Carboplatinum and vincristine for recurrent and newly diagnosed low-grade gliomas of childhood . J Clin Oncol . 1993;;11:850-856.
28 +
Hofman KJ, Harris EL, Bryan N, Denckla M.  Neurofibromatosis type 1: the cognitive phenotype . J Pediatr . 1994;;124:S1-S8.
29 +
Chapman CA, Waber DP, Bassett N, Urion DK, Korf BR.  Neurobehavioral profiles of children with neurofibromatosis 1 referred for learning disabilities are sex-specific . Am J Med Genet . 1996;;67:127-132.
30 +
Zigmond N.  Models for the delivery of special education services to students with learning disabilities in public school . J Child Neurol . 1995;;10:886-892.
31 +
Clementi M, Battistella PA, Rizzi L, Boni S, Tenconi R.  Headache in patients with neurofibromatosis type 1 . Headache . 1996;;36:10.
32 +
Evans DGR, Huson SM, Donnai D, et al.  A clinical study of type 2 neurofibromatosis . Q J Med . 1992;;304:603-618.
33 +
Evans DGR, Huson SM, Donnai D, et al.  A genetic study of type 2 neurofibromatosis in the United Kingdom, I: prevalence, mutation rate, fitness, and confirmation of maternal transmission effect on severity . J Med Genet . 1992;;29:841-846.
34 +
Parry DM, Eldridge R, Kaiser-Kupfer MI, Bouzas EA, Pikus A, Patronas N.  Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity . Am J Med Genet . 1994;;52:450-461.
35 +
Mautner V-F, Lindenau M, Baser ME, et al.  The neuroimaging and clinical spectrum of neurofibromatosis 2 . Neurosurgery . 1996;;38:880-886.
36 +
Ragge NK, Baser ME, Klein J, et al.  Ocular abnormalities in neurofibromatosis 2 . Am J Ophthalmol . 1995;;120:634-641.
37 +
Briggs RJS, Brackmann DE, Baser ME, Hitselberger WE.  Comprehensive management of bilateral acoustic neuromas . Arch Otolaryngol Head Neck Surg . 1994;;120:1307-1314.
38 +
Ojemann RG.  Management of acoustic neuromas (vestibular schwannomas) . Clin Neurosurg . 1993;;40:489-535.
39 +
Nadol J, Chiong C, Ojemann R, et al.  Preservation of hearing and facial nerve function in resection of acoustic neuroma . Laryngoscope . 1992;;102:1153-1158.
40 +
Miyamoto R, Campbell R, Fritsch M, Lochmueller G.  Preservation of hearing in neurofibromatosis 2 . Otolaryngol Head Neck Surg . 1990;;103:619-624.
41 +
Linskey M, Lunsford D, Flickinger J.  Tumor control after stereotactic radiosurgery in neurofibromatosis patients with bilateral acoustic tumors . Neurosurgery . 1992;;31:829-838.
42 +
Lunsford LD, Linskey M.  Stereotactic radiosurgery in the treatment of patients with acoustic tumors . Otolaryngol Clin North Am . 1992;;25:471-491.
43 +
Baser M, MacCollin M, Sujansky E, Evans DGR, Rubenstein A. Malignant nervous system tumors in patients with neurofibromatosis 2. Presented at the 1996 FASEB Summer Research Conference on Neurofibromatosis, Snowmass, Colo, June 29, 1996.
44 +
Kanter WR, Eldridge R, Fabricant R, Allen JC, Koerber T.  Central neurofibromatosis with bilateral acoustic neuroma: genetic, clinical and biochemical distinctions from peripheral neurofibromatosis . Neurology . 1980;;30:851-859.
45 +
Hoffman R, Kohan D, Cohen N.  Cochlear implants in the management of bilateral acoustic neuromas . Am J Otol . 1992;;13:525-528.
46 +
Kayes LM, Riccardi VM, Burke W, Bennett RL, Stephens K.  Large de novo DNA deletion in a patient with sporadic neurofibromatosis, mental retardation and dysmorphism . J Med Genet . 1992;;29:686-690.
47 +
Wu BL, Austin MA, Schneider GH, Boles RG, Korf BR.  Deletion of the entire NF1 gene detected by FISH: four deletion patients associated with severe manifestations . Am J Med Genet . 1995;;59:528-535.
48 +
Ruttledge MH, Andermann AA, Phelan CM, et al.  Type of mutation in the neurofibromatosis type 2 gene (NF2) frequently determines severity of disease . Am J Hum Genet . 1996;;59:331-342.
49 +
Parry DM, MacCollin MM, Kaiser-Kupfer MI, et al.  Germ-line mutations in the neurofibromatosis 2 gene: correlations with disease severity and retinal abnormalities . Am J Hum Genetgroup . 1996;;59:529-539.
50 +
Scoles DR, Baser ME, Pulst S-M.  A missense mutation in the neurofibromatosis 2 gene occurs in patients with mild and severe phenotypes . Neurology . 1996;;47:544-546.
51 +
Arnsmeier SL, Riccardi VM, Paller AS.  Familial multiple cafe-au-lait spots . Arch Dermatol . 1994;;130:1425-1426.
52 +
Charrow J, Listernick R, Ward K.  Autosomal dominant multiple cafe-au-lait spots and neurofibromatosis-1: evidence of non-linkage . Am J Med Genet . 1993;;45:606-608.
53 +
Abelovich D, Gelman-Kohan Z, Silverstein S, et al.  Familial cafe au lait spots: a variant of neurofibromatosis type 1 . J Med Genet . 1995;;32:985-986.
54 +
Sharland M, Burch M, McKenna WM, Paton MA.  A clinical study of Noonan syndrome . Arch Dis Child . 1992;;67:178-183.
55 +
Watson GH.  Pulmonary stenosis, cafe-au-lait spots, and dull intelligence . Arch Dis Child . 1967;;42:303-307.
56 +
Edman Ahlbom B, Dahl N, Zetterqvist P, Anneren G.  Noonan syndrome with cafe-au-lait spots and multiple lentigines syndrome are not linked to-the neurofibromatosis type 1 locus . Clin Genet . 1995;;48:85-89.
57 +
Allanson JE, Upadhyaya M, Watson GH, et al.  Watson syndrome: is it a subtype of type 1 neurofibromatosis? J Med Genet . 1991;;28:752-756.
58 +
MacCollin M, Woodfin W, Kronn D, Short MP.  Schwannomatosis: a clinical and pathologic study . Neurology . 1996;;46:1072-1079.
59 +
Pulst SM, Rouleau GA, Marineau C, Fain P, Sieb JP.  Familial meningioma is not allelic to neurofibromatosis 2 . Neurology . 1993;;43:2096-2098.
60 +
Moss C, Green SH.  What is segmental neurofibromatosis? Br J Dermatol . 1994;;130:106-110.
61 +
Colman SD, Rasmussen SA, Ho VT, Abernathy CR, Wallace MR.  Somatic mosaicism in a patient with neurofibromatosis type 1 . Am J Hum Genet . 1996;;58:484-490.
62 +
Sloan JB, Fretzin DF, Bovenmyer DA.  Genetic counseling in segmental neurofibromatosis . J Am Acad Dermatol . 1990;;22:461-467.
63 +
Heim RA, Silverman LM, Farber RA, KamMorgan LNW, Luce MC.  Screening for truncated NF1 proteins . Nat Genet . 1994;;8:218-219.
64 +
Evans DGR, Bourn D, Wallace A, Ramsden RT, Mitchell JD, Strachan T.  Diagnostic issues in a family with late onset type 2 neurofibromatosis . J Med Genet . 1995;;32:470-474.
65 +
Bourn D, Carter SA, Mason S, Gareth D, Evans R, Strachan T.  Germline mutations in the neurofibromatosis type 2 tumour suppressor gene . Hum Mol Genet . 1994;;3:813-816.
66 +
Merel P, Khe HX, Sanson M, et al.  Screening for germline mutations in the neurofibromatosis 2 gene . Genes Chromosomes Cancer . 1995;;12:117-121.

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The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Note: You must get at least of the answers correct to pass this quiz.
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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
To view and print your certificate and access a summary of your CME courses go to My CME.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s “Cited By” API will populate this tab (http://www.crossref.org/citedby.html).
Compression-Only CPR: Pushing the Science Forward
Cone
AAM 2010;304:1493-1495.
All you need to read in the other general journals
BMJ 2010;341:c5893-c1494.
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