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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Moises Romo M.D.

Overview[edit | edit source]

Neurofibromatosis type 1 is mainly diagnosed clinically. Neurofibromatosis type 1 is usually diagnosed early on in childhood. Genetic testing may be necessary in difficult cases.

Diagnostic Study of Choice[edit | edit source]

Study of choice[edit | edit source]

NF1 is often diagnosed early on in childhood.^[1]

The diagnosis of neurofibromatosis type 1 is mainly clinical.^[2]
Approximately 46% of individuals with a de novo mutation of NF1 gene do not meet criteria the first year of life.^[3]
Annual monitoring until late childhood is necessary for patients with suspicious neurofibromatosis type 1.^[3]
97% of children with one or more features of neurofibromatosis type 1 meet diagnostic criteria by age 8 years.^[3]

National Institute of Health (NIH) Diagnostic Criteria[edit | edit source]

2 of the following 7 "Cardinal Clinical Features" are required for positive diagnosis:^[4]^[5]^[2]

6 or more café-au-lait macules over 5 mm in greatest diameter in pre-pubertal individuals and over 15 mm in greatest diameter in post-pubertal individuals
2 or more neurofibromas of any type or 1 plexiform neurofibroma
Freckling in the axillary or inguinal regions
Optic glioma
2 or more Lisch nodules (iris harmartomas)
A distinctive osseous lesion such as sphenoid dysplasia or thinning of the long bone cortex with or without pseudarthrosis
A first degree relative (parent, sibling, or offspring) with NF1 by the above criteria

Genetic testing[edit | edit source]

In rare occassions where diagnosis is unclear, genetic testing may be necessary.^[2]
Hundreds of mutations in the NF1 gene have beenrecognized; these may be deletions, insertions, splice site mutations, amino acid substitutions, full gene deletions and chromosomal rearrangements.^[6]^[7]
Genetic testing may be necessary for differentiating neurofibromatosis type 1 and Legius syndrome.^[8]^[9]
NF1 gene de novo mutations seem to occur mostly on paternal chromosomes.^[10]^[11]
Neurofibromatosis type 1 is clinically and genetically different from certain tumour predisposition conditions, such as neurofibromatosis type 2 and schwannomatosis.^[8]^[12]^[13]
Genetic testing detects approximately 95% of NF1 mutations in patients that fulfill the clinical diagnostic criteria.^[14]^[7]
Genetic testing does not predict or determines the severity the condition.^[7]
A negative DNA result does not exclude the mutation when there is a known familial mutation.^[7]

References[edit | edit source]

↑ Rad E, Tee AR (April 2016). "Neurofibromatosis type 1: Fundamental insights into cell signalling and cancer". Semin. Cell Dev. Biol. 52: 39–46. doi:10.1016/j.semcdb.2016.02.007. PMID 26860753.
↑ ^2.0 ^2.1 ^2.2 Anderson JL, Gutmann DH (2015). "Neurofibromatosis type 1". Handb Clin Neurol. 132: 75–86. doi:10.1016/B978-0-444-62702-5.00004-4. PMID 26564071.
↑ ^3.0 ^3.1 ^3.2 Ly KI, Blakeley JO (November 2019). "The Diagnosis and Management of Neurofibromatosis Type 1". Med. Clin. North Am. 103 (6): 1035–1054. doi:10.1016/j.mcna.2019.07.004. PMID 31582003.
↑ Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, Rubenstein A, Viskochil D (July 1997). "The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2". JAMA. 278 (1): 51–7. PMID 9207339.
↑ "National Institutes of Health Consensus Development Conference Statement: neurofibromatosis. Bethesda, Md., USA, July 13-15, 1987". Neurofibromatosis. 1 (3): 172–8. 1988. PMID 3152465.
↑ Messiaen L, Riccardi V, Peltonen J, Maertens O, Callens T, Karvonen SL, Leisti EL, Koivunen J, Vandenbroucke I, Stephens K, Pöyhönen M (February 2003). "Independent NF1 mutations in two large families with spinal neurofibromatosis". J. Med. Genet. 40 (2): 122–6. doi:10.1136/jmg.40.2.122. PMC 1735368. PMID 12566521.
↑ ^7.0 ^7.1 ^7.2 ^7.3 Radtke HB, Sebold CD, Allison C, Haidle JL, Schneider G (August 2007). "Neurofibromatosis type 1 in genetic counseling practice: recommendations of the National Society of Genetic Counselors". J Genet Couns. 16 (4): 387–407. doi:10.1007/s10897-007-9101-8. PMC 6338721. PMID 17636453.
↑ ^8.0 ^8.1 Gutmann DH, Ferner RE, Listernick RH, Korf BR, Wolters PL, Johnson KJ (February 2017). "Neurofibromatosis type 1". Nat Rev Dis Primers. 3: 17004. doi:10.1038/nrdp.2017.4. PMID 28230061.
↑ Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP, Parry DM, Eldridge R, Kley N, Menon AG, Pulaski K (March 1993). "A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor". Cell. 72 (5): 791–800. doi:10.1016/0092-8674(93)90406-g. PMID 8453669.
↑ Ainsworth PJ, Chakraborty PK, Weksberg R (1997). "Example of somatic mosaicism in a series of de novo neurofibromatosis type 1 cases due to a maternally derived deletion". Hum. Mutat. 9 (5): 452–7. doi:10.1002/(SICI)1098-1004(1997)9:5<452::AID-HUMU12>3.0.CO;2-1. PMID 9143926.
↑ Upadhyaya M, Ruggieri M, Maynard J, Osborn M, Hartog C, Mudd S, Penttinen M, Cordeiro I, Ponder M, Ponder BA, Krawczak M, Cooper DN (May 1998). "Gross deletions of the neurofibromatosis type 1 (NF1) gene are predominantly of maternal origin and commonly associated with a learning disability, dysmorphic features and developmental delay". Hum. Genet. 102 (5): 591–7. doi:10.1007/s004390050746. PMID 9654211.
↑ Hulsebos TJ, Plomp AS, Wolterman RA, Robanus-Maandag EC, Baas F, Wesseling P (April 2007). "Germline mutation of INI1/SMARCB1 in familial schwannomatosis". Am. J. Hum. Genet. 80 (4): 805–10. doi:10.1086/513207. PMC 1852715. PMID 17357086.
↑ Messiaen L, Yao S, Brems H, Callens T, Sathienkijkanchai A, Denayer E, Spencer E, Arn P, Babovic-Vuksanovic D, Bay C, Bobele G, Cohen BH, Escobar L, Eunpu D, Grebe T, Greenstein R, Hachen R, Irons M, Kronn D, Lemire E, Leppig K, Lim C, McDonald M, Narayanan V, Pearn A, Pedersen R, Powell B, Shapiro LR, Skidmore D, Tegay D, Thiese H, Zackai EH, Vijzelaar R, Taniguchi K, Ayada T, Okamoto F, Yoshimura A, Parret A, Korf B, Legius E (November 2009). "Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome". JAMA. 302 (19): 2111–8. doi:10.1001/jama.2009.1663. PMID 19920235.
↑ Messiaen LM, Callens T, Mortier G, Beysen D, Vandenbroucke I, Van Roy N, Speleman F, Paepe AD (2000). "Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects". Hum. Mutat. 15 (6): 541–55. doi:10.1002/1098-1004(200006)15:6<541::AID-HUMU6>3.0.CO;2-N. PMID 10862084.

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[pmid26860753-1] Rad E, Tee AR (April 2016). "Neurofibromatosis type 1: Fundamental insights into cell signalling and cancer". Semin. Cell Dev. Biol. 52: 39–46. doi:10.1016/j.semcdb.2016.02.007. PMID 26860753.

[pmid26564071-2] 2.0 ^2.1 ^2.2 Anderson JL, Gutmann DH (2015). "Neurofibromatosis type 1". Handb Clin Neurol. 132: 75–86. doi:10.1016/B978-0-444-62702-5.00004-4. PMID 26564071.

[pmid31582003-3] 3.0 ^3.1 ^3.2 Ly KI, Blakeley JO (November 2019). "The Diagnosis and Management of Neurofibromatosis Type 1". Med. Clin. North Am. 103 (6): 1035–1054. doi:10.1016/j.mcna.2019.07.004. PMID 31582003.

[pmid9207339-4] Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, Rubenstein A, Viskochil D (July 1997). "The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2". JAMA. 278 (1): 51–7. PMID 9207339.

[pmid3152465-5] "National Institutes of Health Consensus Development Conference Statement: neurofibromatosis. Bethesda, Md., USA, July 13-15, 1987". Neurofibromatosis. 1 (3): 172–8. 1988. PMID 3152465.

[pmid12566521-6] Messiaen L, Riccardi V, Peltonen J, Maertens O, Callens T, Karvonen SL, Leisti EL, Koivunen J, Vandenbroucke I, Stephens K, Pöyhönen M (February 2003). "Independent NF1 mutations in two large families with spinal neurofibromatosis". J. Med. Genet. 40 (2): 122–6. doi:10.1136/jmg.40.2.122. PMC 1735368. PMID 12566521.

[pmid17636453-7] 7.0 ^7.1 ^7.2 ^7.3 Radtke HB, Sebold CD, Allison C, Haidle JL, Schneider G (August 2007). "Neurofibromatosis type 1 in genetic counseling practice: recommendations of the National Society of Genetic Counselors". J Genet Couns. 16 (4): 387–407. doi:10.1007/s10897-007-9101-8. PMC 6338721. PMID 17636453.

[pmid28230061-8] 8.0 ^8.1 Gutmann DH, Ferner RE, Listernick RH, Korf BR, Wolters PL, Johnson KJ (February 2017). "Neurofibromatosis type 1". Nat Rev Dis Primers. 3: 17004. doi:10.1038/nrdp.2017.4. PMID 28230061.

[pmid8453669-9] Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP, Parry DM, Eldridge R, Kley N, Menon AG, Pulaski K (March 1993). "A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor". Cell. 72 (5): 791–800. doi:10.1016/0092-8674(93)90406-g. PMID 8453669.

[pmid9143926-10] Ainsworth PJ, Chakraborty PK, Weksberg R (1997). "Example of somatic mosaicism in a series of de novo neurofibromatosis type 1 cases due to a maternally derived deletion". Hum. Mutat. 9 (5): 452–7. doi:10.1002/(SICI)1098-1004(1997)9:5<452::AID-HUMU12>3.0.CO;2-1. PMID 9143926.

[pmid9654211-11] Upadhyaya M, Ruggieri M, Maynard J, Osborn M, Hartog C, Mudd S, Penttinen M, Cordeiro I, Ponder M, Ponder BA, Krawczak M, Cooper DN (May 1998). "Gross deletions of the neurofibromatosis type 1 (NF1) gene are predominantly of maternal origin and commonly associated with a learning disability, dysmorphic features and developmental delay". Hum. Genet. 102 (5): 591–7. doi:10.1007/s004390050746. PMID 9654211.

[pmid17357086-12] Hulsebos TJ, Plomp AS, Wolterman RA, Robanus-Maandag EC, Baas F, Wesseling P (April 2007). "Germline mutation of INI1/SMARCB1 in familial schwannomatosis". Am. J. Hum. Genet. 80 (4): 805–10. doi:10.1086/513207. PMC 1852715. PMID 17357086.

[pmid19920235-13] Messiaen L, Yao S, Brems H, Callens T, Sathienkijkanchai A, Denayer E, Spencer E, Arn P, Babovic-Vuksanovic D, Bay C, Bobele G, Cohen BH, Escobar L, Eunpu D, Grebe T, Greenstein R, Hachen R, Irons M, Kronn D, Lemire E, Leppig K, Lim C, McDonald M, Narayanan V, Pearn A, Pedersen R, Powell B, Shapiro LR, Skidmore D, Tegay D, Thiese H, Zackai EH, Vijzelaar R, Taniguchi K, Ayada T, Okamoto F, Yoshimura A, Parret A, Korf B, Legius E (November 2009). "Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome". JAMA. 302 (19): 2111–8. doi:10.1001/jama.2009.1663. PMID 19920235.

[pmid10862084-14] Messiaen LM, Callens T, Mortier G, Beysen D, Vandenbroucke I, Van Roy N, Speleman F, Paepe AD (2000). "Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects". Hum. Mutat. 15 (6): 541–55. doi:10.1002/1098-1004(200006)15:6<541::AID-HUMU6>3.0.CO;2-N. PMID 10862084.

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