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Nörofibromatozis tip 1 yeni tanı kriterlerine sahip çocukluk çağındaki hastaların klinik ve moleküler özellikleri

Year 2024, Volume: 63 Issue: 1, 115 - 123, 19.03.2024

Burcu Yeter Doğan , Yasemin Kendir Demirkol

https://doi.org/10.19161/etd.1200311

Abstract

Amaç: Nörofibromatozis tip 1 cafe-au-lait makülleri, koltuk altı ve inguinal bölgelerde çillenme, Lisch nodülleri ve kutanöz veya pleksiform nörofibromlar ile karakterize sık görülen otozomal dominant kalıtımlı, nörokutanöz genetik bir hastalıktır. Son yıllarda Nörofibromatozis tip 1 yeni tanı kriterleri geliştirilmiş olup çalışmamızda bu güncellenen tanı kriterleri ile çocukluk çağındaki hastaların klinik ve moleküler özelliklerinin geriye dönük olarak değerlendirilmesi ve fenotip-genotip korelasyonu yapılması amaçlanmıştır.
Gereç ve Yöntem: Nörofibromatozis tip 1 ön tanısı ile çocuk genetik polikliniğine başvuran ve NF1 geni dizi analizinde patojenik varyant saptanan pediatrik yaş grubundaki toplam 21 hastanın klinik ve moleküler bulguları retrospektif olarak incelenmiştir.
Bulgular: Hastaların NF1 gen dizi analizleri sonucunda dokuz anlamsız, altı çerçeve kayması, beş kırpılma bölgesi varyantı ve bir de tüm gen delesyonu tespit edilmiştir. Bunlardan üçü ise daha önce bildirilmemiş yeni varyanttır. Hastaların hepsinde cafe-au-lait makülleri mevcut olup yaklaşık yarısında da koltuk altı ya da kasık bölgesinde çillenme vardı. 3 olguda cilt nörofibromu, 1 olguda ise Lisch nodülü gözlendi. Eski ve yeni tanı kriterleri karşılaştırıldığında hastaların 16’sı eski tanı kriterlerini karşılarken yeni tanı kriterlerine göre hastaların tamamı tanı almıştır.
Sonuç: Yeni tanı kriterleri hastaların tanı alma oranını önemli derecede yükseltmiştir. Çalışmamızdaki hastaların tamamı yeni tanı kriterlerini karşılamıştır. Bu durum küçük yaşlarda tanı kriterlerini karşılamayan hastalarda NF1 moleküler analizinin önemini göstermektedir. Ayrıca bu çalışmayla daha önce tanımlanmamış üç yeni varyantla birlikte NF1 mutasyon spektrumunu genişlettik.

Keywords

cafe-au-lait NF1 Nörofibromatozis1 yeni nesil dizileme

References

  • Referans1. Anderson, J.L. and D.H. Gutmann, Neurofibromatosis type 1. Handb Clin Neurol, 2015. 132: p. 75-86.
  • Referans2 Lammert, M., et al., Prevalence of neurofibromatosis 1 in German children at elementary school enrollment. Arch Dermatol, 2005. 141(1): p. 71-4.
  • Referans3 Ferner, R.E. and D.H. Gutmann, Neurofibromatosis type 1 (NF1): diagnosis and management. Handb Clin Neurol, 2013. 115: p. 939-55.
  • Referans4 Ferner, R.E., et al., Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet, 2007. 44(2): p. 81-8.
  • Referans5 Evans, D.G.R., et al., Breast cancer in neurofibromatosis 1: survival and risk of contralateral breast cancer in a five country cohort study. Genet Med, 2020. 22(2): p. 398-406.
  • Referans6 Uusitalo, E., et al., Distinctive Cancer Associations in Patients With Neurofibromatosis Type 1. J Clin Oncol, 2016. 34(17): p. 1978-86.
  • Referans7 Gutmann, D.H., et al., The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA, 1997. 278(1): p. 51-7.
  • Referans8 Valero, M.C., et al., Identification of de novo deletions at the NF1 gene: no preferential paternal origin and phenotypic analysis of patients. Hum Genet, 1997. 99(6): p. 720-6.
  • Referans9 Friedman, J.M., Neurofibromatosis 1, in GeneReviews((R)), M.P. Adam, et al., Editors. 1993: Seattle (WA).
  • Referans10 Bergoug, M., et al., Neurofibromin Structure, Functions and Regulation. Cells, 2020. 9(11).
  • Referans11 Gutmann, D.H., et al., Neurofibromatosis type 1. Nat Rev Dis Primers, 2017. 3: p. 17004.
  • Referans12 Koczkowska, M., et al., Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1. Hum Mutat, 2020. 41(1): p. 299-315.
  • Referans13 Marchuk, D.A., et al., cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product. Genomics, 1991. 11(4): p. 931-40.
  • Referans14 Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol, 1988. 45(5): p. 575-8.
  • Referans15 Legius, E., et al., Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med, 2021. 23(8): p. 1506-1513.
  • Referans16 Barrea, C., et al., Phenotype-Genotype Correlation in Children with Neurofibromatosis Type 1. Neuropediatrics, 2018. 49(3): p. 180-184.
  • Referans17 Gunes, N., et al., Neurofibromatosis type 1: Expanded variant spectrum with multiplex ligation-dependent probe amplification and genotype-phenotype correlation in 138 Turkish patients. Ann Hum Genet, 2021. 85(5): p. 155-165.
  • Referans18 Ben-Salem, S., et al., The mutational spectrum of the NF1 gene in neurofibromatosis type I patients from UAE. Childs Nerv Syst, 2014. 30(7): p. 1183-9.
  • Referans19 Cnossen, M.H., et al., A prospective 10 year follow up study of patients with neurofibromatosis type 1. Arch Dis Child, 1998. 78(5): p. 408-12.
  • Referans20 Nunley, K.S., et al., Predictive value of cafe au lait macules at initial consultation in the diagnosis of neurofibromatosis type 1. Arch Dermatol, 2009. 145(8): p. 883-7.
  • Referans21 Lubs, M.L., et al., Lisch nodules in neurofibromatosis type 1. N Engl J Med, 1991. 324(18): p. 1264-6.
  • Referans22 Cassiman, C., et al., Choroidal abnormalities in cafe-au-lait syndromes: a new differential diagnostic tool? Clin Genet, 2017. 91(4): p. 529-535.
  • Referans23 Vagge, A., et al., Choroidal abnormalities in neurofibromatosis type 1 detected by near-infrared reflectance imaging in paediatric population. Acta Ophthalmol, 2015. 93(8): p. e667-71.
  • Referans24 Viola, F., et al., Choroidal abnormalities detected by near-infrared reflectance imaging as a new diagnostic criterion for neurofibromatosis 1. Ophthalmology, 2012. 119(2): p. 369-75.
  • Referans25 Goktas, S., et al., Frequency of choroidal abnormalities in pediatric patients with neurofibromatosis type 1. J Pediatr Ophthalmol Strabismus, 2014. 51(4): p. 204-8.
  • Referans26 Gutmann, D.H., et al., Gliomas presenting after age 10 in individuals with neurofibromatosis type 1 (NF1). Neurology, 2002. 59(5): p. 759-61.
  • Referans27 Ullrich, N.J., et al., Brainstem lesions in neurofibromatosis type 1. Neurosurgery, 2007. 61(4): p. 762-6; discussion 766-7.
  • Referans28 Alwan, S., S.J. Tredwell, and J.M. Friedman, Is osseous dysplasia a primary feature of neurofibromatosis 1 (NF1)? Clin Genet, 2005. 67(5): p. 378-90.
  • Referans29 Avery, R.A., et al., Orbital/Periorbital Plexiform Neurofibromas in Children with Neurofibromatosis Type 1: Multidisciplinary Recommendations for Care. Ophthalmology, 2017. 124(1): p. 123-132.
  • Referans30 Oliveira, T.E., R.G. Tarle, and L.A.F. Mesquita, Dermoscopy in the diagnosis of juvenile xanthogranuloma. An Bras Dermatol, 2018. 93(1): p. 138-140.
  • Referans31 Szczerkowska-Dobosz, A., et al., Juvenile xanthogranuloma: a rare benign histiocytic disorder. Postepy Dermatol Alergol, 2014. 31(3): p. 197-200.
  • Referans32 Cambiaghi, S., L. Restano, and R. Caputo, Juvenile xanthogranuloma associated with neurofibromatosis 1: 14 patients without evidence of hematologic malignancies. Pediatr Dermatol, 2004. 21(2): p. 97-101.
  • Referans33 Ferrari, F., et al., Juvenile xanthogranuloma and nevus anemicus in the diagnosis of neurofibromatosis type 1. JAMA Dermatol, 2014. 150(1): p. 42-6.
  • Referans34 Zvulunov, A., Y. Barak, and A. Metzker, Juvenile xanthogranuloma, neurofibromatosis, and juvenile chronic myelogenous leukemia. World statistical analysis. Arch Dermatol, 1995. 131(8): p. 904-8.
  • Referans35 Chen, L., et al., Five novel NF1 gene pathogenic variants in 10 different Chinese families with neurofibromatosis type 1. Mol Genet Genomic Med, 2019. 7(9): p. e904.
  • Referans36 Ece Solmaz, A., et al., Mutation spectrum of the NF1 gene and genotype-phenotype correlations in Turkish patients: Seventeen novel pathogenic variants. Clin Neurol Neurosurg, 2021. 208: p. 106884.
  • Referans37 Schotland, H.M., et al., Neurofibromatosis 1 and osseous fibrous dysplasia in a family. Am J Med Genet, 1992. 43(5): p. 815-22.
  • Referans38 Pasmant, E., et al., NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype. Hum Mutat, 2010. 31(6): p. E1506-18.
  • Referans39 Koczkowska, M., et al., Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation. Genet Med, 2019. 21(4): p. 867-876.
  • Referans40 Castle, B., et al., Evaluation of genotype-phenotype correlations in neurofibromatosis type 1. J Med Genet, 2003. 40(10): p. e109.

Clinical and molecular characteristics of pediatric patients with neurofibromatosis type 1 new diagnostic criteria

Year 2024, Volume: 63 Issue: 1, 115 - 123, 19.03.2024

Burcu Yeter Doğan , Yasemin Kendir Demirkol

https://doi.org/10.19161/etd.1200311

Abstract

Aim: Neurofibromatosis type 1 is a common autosomal dominant inherited neurocutaneous genetic disease characterized by cafe-au-lait macules, axillary and inguinal freckling, Lisch nodules, and cutaneous or plexiform neurofibromas. New diagnostic criteria for Neurofibromatosis type 1 have been developed in recent years. Our study aims to retrospectively evaluate childhood patients' clinical and molecular characteristics and make a phenotype-genotype correlation with these updated diagnostic criteria.
Materials and Methods: The clinical and molecular findings of 21 patients in the pediatric age group who were admitted to the pediatric genetics outpatient clinic with a preliminary diagnosis of neurofibromatosis type 1 and who were also found to have a pathogenic variant in the NF1 gene sequence analysis were retrospectively analyzed.
Results: As a result of the NF1 gene sequence analysis of the patients, nine nonsense, six frameshift, five splice site variants, and one whole gene deletion were detected. Three of these are novel variants that have not been reported before. All the patients had cafe-au-lait macules, and about half of them had freckles in the armpit or groin area. In addition, skin neurofibroma was observed in three cases, and Lisch nodule was observed in one case. When the old and new diagnostic criteria were compared, 16 of the patients met the old diagnostic criteria, while all the patients were diagnosed according to the new diagnostic criteria.
Conclusion: The new diagnostic criteria have significantly increased the diagnosis rate of patients. All of the patients in our study met the new diagnostic criteria. This shows the importance of NF1 molecular analysis in patients who do not meet the diagnostic criteria at an early age. We also expanded the NF1 mutation spectrum with this study, with three new variants not previously identified.

Keywords

Cafe-au-lait spot neurofibromatosis NF1 next-generation sequencing

References

  • Referans1. Anderson, J.L. and D.H. Gutmann, Neurofibromatosis type 1. Handb Clin Neurol, 2015. 132: p. 75-86.
  • Referans2 Lammert, M., et al., Prevalence of neurofibromatosis 1 in German children at elementary school enrollment. Arch Dermatol, 2005. 141(1): p. 71-4.
  • Referans3 Ferner, R.E. and D.H. Gutmann, Neurofibromatosis type 1 (NF1): diagnosis and management. Handb Clin Neurol, 2013. 115: p. 939-55.
  • Referans4 Ferner, R.E., et al., Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet, 2007. 44(2): p. 81-8.
  • Referans5 Evans, D.G.R., et al., Breast cancer in neurofibromatosis 1: survival and risk of contralateral breast cancer in a five country cohort study. Genet Med, 2020. 22(2): p. 398-406.
  • Referans6 Uusitalo, E., et al., Distinctive Cancer Associations in Patients With Neurofibromatosis Type 1. J Clin Oncol, 2016. 34(17): p. 1978-86.
  • Referans7 Gutmann, D.H., et al., The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA, 1997. 278(1): p. 51-7.
  • Referans8 Valero, M.C., et al., Identification of de novo deletions at the NF1 gene: no preferential paternal origin and phenotypic analysis of patients. Hum Genet, 1997. 99(6): p. 720-6.
  • Referans9 Friedman, J.M., Neurofibromatosis 1, in GeneReviews((R)), M.P. Adam, et al., Editors. 1993: Seattle (WA).
  • Referans10 Bergoug, M., et al., Neurofibromin Structure, Functions and Regulation. Cells, 2020. 9(11).
  • Referans11 Gutmann, D.H., et al., Neurofibromatosis type 1. Nat Rev Dis Primers, 2017. 3: p. 17004.
  • Referans12 Koczkowska, M., et al., Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1. Hum Mutat, 2020. 41(1): p. 299-315.
  • Referans13 Marchuk, D.A., et al., cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product. Genomics, 1991. 11(4): p. 931-40.
  • Referans14 Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol, 1988. 45(5): p. 575-8.
  • Referans15 Legius, E., et al., Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med, 2021. 23(8): p. 1506-1513.
  • Referans16 Barrea, C., et al., Phenotype-Genotype Correlation in Children with Neurofibromatosis Type 1. Neuropediatrics, 2018. 49(3): p. 180-184.
  • Referans17 Gunes, N., et al., Neurofibromatosis type 1: Expanded variant spectrum with multiplex ligation-dependent probe amplification and genotype-phenotype correlation in 138 Turkish patients. Ann Hum Genet, 2021. 85(5): p. 155-165.
  • Referans18 Ben-Salem, S., et al., The mutational spectrum of the NF1 gene in neurofibromatosis type I patients from UAE. Childs Nerv Syst, 2014. 30(7): p. 1183-9.
  • Referans19 Cnossen, M.H., et al., A prospective 10 year follow up study of patients with neurofibromatosis type 1. Arch Dis Child, 1998. 78(5): p. 408-12.
  • Referans20 Nunley, K.S., et al., Predictive value of cafe au lait macules at initial consultation in the diagnosis of neurofibromatosis type 1. Arch Dermatol, 2009. 145(8): p. 883-7.
  • Referans21 Lubs, M.L., et al., Lisch nodules in neurofibromatosis type 1. N Engl J Med, 1991. 324(18): p. 1264-6.
  • Referans22 Cassiman, C., et al., Choroidal abnormalities in cafe-au-lait syndromes: a new differential diagnostic tool? Clin Genet, 2017. 91(4): p. 529-535.
  • Referans23 Vagge, A., et al., Choroidal abnormalities in neurofibromatosis type 1 detected by near-infrared reflectance imaging in paediatric population. Acta Ophthalmol, 2015. 93(8): p. e667-71.
  • Referans24 Viola, F., et al., Choroidal abnormalities detected by near-infrared reflectance imaging as a new diagnostic criterion for neurofibromatosis 1. Ophthalmology, 2012. 119(2): p. 369-75.
  • Referans25 Goktas, S., et al., Frequency of choroidal abnormalities in pediatric patients with neurofibromatosis type 1. J Pediatr Ophthalmol Strabismus, 2014. 51(4): p. 204-8.
  • Referans26 Gutmann, D.H., et al., Gliomas presenting after age 10 in individuals with neurofibromatosis type 1 (NF1). Neurology, 2002. 59(5): p. 759-61.
  • Referans27 Ullrich, N.J., et al., Brainstem lesions in neurofibromatosis type 1. Neurosurgery, 2007. 61(4): p. 762-6; discussion 766-7.
  • Referans28 Alwan, S., S.J. Tredwell, and J.M. Friedman, Is osseous dysplasia a primary feature of neurofibromatosis 1 (NF1)? Clin Genet, 2005. 67(5): p. 378-90.
  • Referans29 Avery, R.A., et al., Orbital/Periorbital Plexiform Neurofibromas in Children with Neurofibromatosis Type 1: Multidisciplinary Recommendations for Care. Ophthalmology, 2017. 124(1): p. 123-132.
  • Referans30 Oliveira, T.E., R.G. Tarle, and L.A.F. Mesquita, Dermoscopy in the diagnosis of juvenile xanthogranuloma. An Bras Dermatol, 2018. 93(1): p. 138-140.
  • Referans31 Szczerkowska-Dobosz, A., et al., Juvenile xanthogranuloma: a rare benign histiocytic disorder. Postepy Dermatol Alergol, 2014. 31(3): p. 197-200.
  • Referans32 Cambiaghi, S., L. Restano, and R. Caputo, Juvenile xanthogranuloma associated with neurofibromatosis 1: 14 patients without evidence of hematologic malignancies. Pediatr Dermatol, 2004. 21(2): p. 97-101.
  • Referans33 Ferrari, F., et al., Juvenile xanthogranuloma and nevus anemicus in the diagnosis of neurofibromatosis type 1. JAMA Dermatol, 2014. 150(1): p. 42-6.
  • Referans34 Zvulunov, A., Y. Barak, and A. Metzker, Juvenile xanthogranuloma, neurofibromatosis, and juvenile chronic myelogenous leukemia. World statistical analysis. Arch Dermatol, 1995. 131(8): p. 904-8.
  • Referans35 Chen, L., et al., Five novel NF1 gene pathogenic variants in 10 different Chinese families with neurofibromatosis type 1. Mol Genet Genomic Med, 2019. 7(9): p. e904.
  • Referans36 Ece Solmaz, A., et al., Mutation spectrum of the NF1 gene and genotype-phenotype correlations in Turkish patients: Seventeen novel pathogenic variants. Clin Neurol Neurosurg, 2021. 208: p. 106884.
  • Referans37 Schotland, H.M., et al., Neurofibromatosis 1 and osseous fibrous dysplasia in a family. Am J Med Genet, 1992. 43(5): p. 815-22.
  • Referans38 Pasmant, E., et al., NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype. Hum Mutat, 2010. 31(6): p. E1506-18.
  • Referans39 Koczkowska, M., et al., Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation. Genet Med, 2019. 21(4): p. 867-876.
  • Referans40 Castle, B., et al., Evaluation of genotype-phenotype correlations in neurofibromatosis type 1. J Med Genet, 2003. 40(10): p. e109.
There are 40 citations in total.

Details

Primary Language Turkish
Subjects Health Care Administration
Journal Section Research Articles
Authors

Burcu Yeter Doğan 0000-0002-6255-1057

Yasemin Kendir Demirkol 0000-0001-8016-5224

Publication Date March 19, 2024
Submission Date November 15, 2022
Published in Issue Year 2024Volume: 63 Issue: 1

Cite

Vancouver Yeter Doğan B, Kendir Demirkol Y. Nörofibromatozis tip 1 yeni tanı kriterlerine sahip çocukluk çağındaki hastaların klinik ve moleküler özellikleri. EJM. 2024;63(1):115-23.
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