Case Series: Neurofibromatosis Type 1 in 8 Pediatric Patients; Genotype and Phenotype Analysis

Afërdita Tako Kumaraku; Kristi Aleksi; Aida Bushati; Armand Shehu; Blerina Saraçi; Renald Meçani; Paskal Cullufi

doi:doi:10.11648/j.ijmcr.20230202.11

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Case Series: Neurofibromatosis Type 1 in 8 Pediatric Patients; Genotype and Phenotype Analysis

Afërdita Tako Kumaraku, Kristi Aleksi, Aida Bushati, Armand Shehu, Blerina Saraçi, Renald Meçani, Paskal Cullufi

Published in International Journal of Medical Case Reports (Volume 2, Issue 2)

Received: 7 April 2023 Accepted: 2 May 2023 Published: 17 May 2023

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Abstract

Neurofibromatosis type I is a multi-systemic disorder caused by variants in the neurofibromin, a gene on chromosome 17 that regulates a variety of cellular functions important for tumorigenesis. Clinically it is characterized by multiple café-au-lait spots, intertriginous freckling, neurofibromas, and learning disability or behavior problems. Neurofibromatosis type I is inherited in an autosomal dominant manner, but approximately half of those afflicted have the condition as a result of a de novo disease-causing variant. In this case series, we present 8 pediatric patients at Mother Teresa University Hospital Center in Tirana, Albania whose genetic diagnosis was confirmed by Whole exome sequencing including Next-generation sequencing-based Copy number variation analysis. Based on our clinical findings, they all meet the revised clinical diagnostic criteria of Neurofibromatosis type I by the International Consensus Conference held in 2021. In 5 of them, the variant was inherited from one of the parents, while in the remaining 3 the variant was de novo. Herein we discuss each genotype detected, the coordinates, class, and the modifications they induce in the neurofibromin protein. We also discuss our patients’ phenotypes; the cases of two pairs of siblings with identical inherited variants but with different clinical manifestations caught our interest, but studies confirm that the phenotype varies even among individuals with identical variants. In the end, identifying the signs and symptoms early and with certainty and rapidly assigning the cases to qualified healthcare professionals is important for patients with neurofibromatosis type I.

Published in	International Journal of Medical Case Reports (Volume 2, Issue 2)
DOI	10.11648/j.ijmcr.20230202.11
Page(s)	8-11
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2023. Published by Science Publishing Group

Keywords

Neurofibromatosis 1, NF1, Rare Diseases, Pediatric Patients

References

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[2]	Upadhyaya M, Cooper DN, editors. Neurofibromatosis type 1: molecular and cellular biology. Springer Science & Business Media; 2013.
[3]	Peltonen S, Kallionpää RA, Peltonen J. Neurofibromatosis type 1 (NF1) gene: Beyond café au lait spots and dermal neurofibromas. Experimental Dermatology. 2016; 26 (7): 645–8.
[4]	Scheffzek K, Welti S. Neurofibromin: Protein Domains and Functional Characteristics. Neurofibromatosis Type 1. 2012; 305–26.
[5]	Molina JR, Adjei AA. The Ras/Raf/MAPK Pathway. Journal of Thoracic Oncology. 2006; 1 (1): 7–9.
[6]	Cary LA, Han DC, Guan JL. Invited Reviews-Integrin-mediated signal transduction pathways. Histology and histopathology. 1999; 14 (3): 1001.
[7]	Friedman JM. Neurofibromatosis 1. Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, et al., editors. PubMed. Seattle (WA): University of Washington, Seattle; 1993.
[8]	Evans DG, Howard E, Giblin C, Clancy T, Spencer H, Huson SM, et al. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. American Journal of Medical Genetics Part A. 2010; 152A (2): 327–32.
[9]	von Recklinghausen FD. Uber die multiplen Fibome der Haut und ihre Beziehung zu den multiplen Neuromen. Berlin Virchows Hirschward. 1882: 1-41.
[10]	Bettegowda C, Upadhayaya M, Evans DG, Kim A, Mathios D, Hanemann CO. Genotype-Phenotype Correlations in Neurofibromatosis and Their Potential Clinical Use. Neurology. 2021; 97 (7 Supplement 1): S91–8.
[11]	Upadhyaya M, Huson SM, Davies M, et al. An absence of cutaneous neurofibromas associated with a 3-bp in-frame deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet. 2007; 80 (1): 140–151.
[12]	Xiong HY, Alipanahi B, Lee LJ, Bretschneider H, Merico D, Yuen RKC, et al. The human splicing code reveals new insights into the genetic determinants of disease. Science [Internet]. 2014; 347 (6218): 1254806–6.
[13]	Tsipi M, Poulou M, Fylaktou I, Kosma K, Tsoutsou E, Pons MR, et al. Phenotypic expression of a spectrum of Neurofibromatosis Type 1 (NF1) mutations identified through NGS and MLPA. Journal of the Neurological Sciences. 2018; 395: 95–105.
[14]	Wimmer K, Eckart M, Stadler PF, Rehder H, Fonatsch C. Three different premature stop codons lead to skipping of exon 7 in neurofibromatosis type I patients. Human Mutation. 2000; 16 (1): 90-1.
[15]	Zatkova A, Messiaen L, Vandenbroucke I, Wieser R, Fonatsch C, Krainer AR, et al. Disruption of exonic splicing enhancer elements is the principal cause of exon skipping associated with seven nonsense or missense alleles of NF1. Human Mutation. 2004; 24 (6): 491–501.

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APA Style

Afërdita Tako Kumaraku, Kristi Aleksi, Aida Bushati, Armand Shehu, Blerina Saraçi, et al. (2023). Case Series: Neurofibromatosis Type 1 in 8 Pediatric Patients; Genotype and Phenotype Analysis. International Journal of Medical Case Reports, 2(2), 8-11. https://doi.org/10.11648/j.ijmcr.20230202.11

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ACS Style

Afërdita Tako Kumaraku; Kristi Aleksi; Aida Bushati; Armand Shehu; Blerina Saraçi, et al. Case Series: Neurofibromatosis Type 1 in 8 Pediatric Patients; Genotype and Phenotype Analysis. Int. J. Med. Case Rep. 2023, 2(2), 8-11. doi: 10.11648/j.ijmcr.20230202.11

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AMA Style

Afërdita Tako Kumaraku, Kristi Aleksi, Aida Bushati, Armand Shehu, Blerina Saraçi, et al. Case Series: Neurofibromatosis Type 1 in 8 Pediatric Patients; Genotype and Phenotype Analysis. Int J Med Case Rep. 2023;2(2):8-11. doi: 10.11648/j.ijmcr.20230202.11

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@article{10.11648/j.ijmcr.20230202.11,
  author = {Afërdita Tako Kumaraku and Kristi Aleksi and Aida Bushati and Armand Shehu and Blerina Saraçi and Renald Meçani and Paskal Cullufi},
  title = {Case Series: Neurofibromatosis Type 1 in 8 Pediatric Patients; Genotype and Phenotype Analysis},
  journal = {International Journal of Medical Case Reports},
  volume = {2},
  number = {2},
  pages = {8-11},
  doi = {10.11648/j.ijmcr.20230202.11},
  url = {https://doi.org/10.11648/j.ijmcr.20230202.11},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ijmcr.20230202.11},
  abstract = {Neurofibromatosis type I is a multi-systemic disorder caused by variants in the neurofibromin, a gene on chromosome 17 that regulates a variety of cellular functions important for tumorigenesis. Clinically it is characterized by multiple café-au-lait spots, intertriginous freckling, neurofibromas, and learning disability or behavior problems. Neurofibromatosis type I is inherited in an autosomal dominant manner, but approximately half of those afflicted have the condition as a result of a de novo disease-causing variant. In this case series, we present 8 pediatric patients at Mother Teresa University Hospital Center in Tirana, Albania whose genetic diagnosis was confirmed by Whole exome sequencing including Next-generation sequencing-based Copy number variation analysis. Based on our clinical findings, they all meet the revised clinical diagnostic criteria of Neurofibromatosis type I by the International Consensus Conference held in 2021. In 5 of them, the variant was inherited from one of the parents, while in the remaining 3 the variant was de novo. Herein we discuss each genotype detected, the coordinates, class, and the modifications they induce in the neurofibromin protein. We also discuss our patients’ phenotypes; the cases of two pairs of siblings with identical inherited variants but with different clinical manifestations caught our interest, but studies confirm that the phenotype varies even among individuals with identical variants. In the end, identifying the signs and symptoms early and with certainty and rapidly assigning the cases to qualified healthcare professionals is important for patients with neurofibromatosis type I.},
 year = {2023}
}

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TY  - JOUR
T1  - Case Series: Neurofibromatosis Type 1 in 8 Pediatric Patients; Genotype and Phenotype Analysis
AU  - Afërdita Tako Kumaraku
AU  - Kristi Aleksi
AU  - Aida Bushati
AU  - Armand Shehu
AU  - Blerina Saraçi
AU  - Renald Meçani
AU  - Paskal Cullufi
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PY  - 2023
N1  - https://doi.org/10.11648/j.ijmcr.20230202.11
DO  - 10.11648/j.ijmcr.20230202.11
T2  - International Journal of Medical Case Reports
JF  - International Journal of Medical Case Reports
JO  - International Journal of Medical Case Reports
SP  - 8
EP  - 11
PB  - Science Publishing Group
SN  - 2994-7049
UR  - https://doi.org/10.11648/j.ijmcr.20230202.11
AB  - Neurofibromatosis type I is a multi-systemic disorder caused by variants in the neurofibromin, a gene on chromosome 17 that regulates a variety of cellular functions important for tumorigenesis. Clinically it is characterized by multiple café-au-lait spots, intertriginous freckling, neurofibromas, and learning disability or behavior problems. Neurofibromatosis type I is inherited in an autosomal dominant manner, but approximately half of those afflicted have the condition as a result of a de novo disease-causing variant. In this case series, we present 8 pediatric patients at Mother Teresa University Hospital Center in Tirana, Albania whose genetic diagnosis was confirmed by Whole exome sequencing including Next-generation sequencing-based Copy number variation analysis. Based on our clinical findings, they all meet the revised clinical diagnostic criteria of Neurofibromatosis type I by the International Consensus Conference held in 2021. In 5 of them, the variant was inherited from one of the parents, while in the remaining 3 the variant was de novo. Herein we discuss each genotype detected, the coordinates, class, and the modifications they induce in the neurofibromin protein. We also discuss our patients’ phenotypes; the cases of two pairs of siblings with identical inherited variants but with different clinical manifestations caught our interest, but studies confirm that the phenotype varies even among individuals with identical variants. In the end, identifying the signs and symptoms early and with certainty and rapidly assigning the cases to qualified healthcare professionals is important for patients with neurofibromatosis type I.
VL  - 2
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ER  -

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Author Information

Afërdita Tako Kumaraku
Kristi Aleksi

Faculty of Medicine, University of Medicine, Tirana, Albania
Aida Bushati

Service of Pediatrics, Mother Teresa University Hospital Center, Tirana, Albania
Armand Shehu

Service of Pediatrics, Mother Teresa University Hospital Center, Tirana, Albania
Blerina Saraçi
Renald Meçani
Paskal Cullufi

Service of Pediatrics, Mother Teresa University Hospital Center, Tirana, Albania

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APA Style

Afërdita Tako Kumaraku, Kristi Aleksi, Aida Bushati, Armand Shehu, Blerina Saraçi, et al. (2023). Case Series: Neurofibromatosis Type 1 in 8 Pediatric Patients; Genotype and Phenotype Analysis. International Journal of Medical Case Reports, 2(2), 8-11. https://doi.org/10.11648/j.ijmcr.20230202.11

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ACS Style

Afërdita Tako Kumaraku; Kristi Aleksi; Aida Bushati; Armand Shehu; Blerina Saraçi, et al. Case Series: Neurofibromatosis Type 1 in 8 Pediatric Patients; Genotype and Phenotype Analysis. Int. J. Med. Case Rep. 2023, 2(2), 8-11. doi: 10.11648/j.ijmcr.20230202.11

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AMA Style

Afërdita Tako Kumaraku, Kristi Aleksi, Aida Bushati, Armand Shehu, Blerina Saraçi, et al. Case Series: Neurofibromatosis Type 1 in 8 Pediatric Patients; Genotype and Phenotype Analysis. Int J Med Case Rep. 2023;2(2):8-11. doi: 10.11648/j.ijmcr.20230202.11

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@article{10.11648/j.ijmcr.20230202.11,
  author = {Afërdita Tako Kumaraku and Kristi Aleksi and Aida Bushati and Armand Shehu and Blerina Saraçi and Renald Meçani and Paskal Cullufi},
  title = {Case Series: Neurofibromatosis Type 1 in 8 Pediatric Patients; Genotype and Phenotype Analysis},
  journal = {International Journal of Medical Case Reports},
  volume = {2},
  number = {2},
  pages = {8-11},
  doi = {10.11648/j.ijmcr.20230202.11},
  url = {https://doi.org/10.11648/j.ijmcr.20230202.11},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ijmcr.20230202.11},
  abstract = {Neurofibromatosis type I is a multi-systemic disorder caused by variants in the neurofibromin, a gene on chromosome 17 that regulates a variety of cellular functions important for tumorigenesis. Clinically it is characterized by multiple café-au-lait spots, intertriginous freckling, neurofibromas, and learning disability or behavior problems. Neurofibromatosis type I is inherited in an autosomal dominant manner, but approximately half of those afflicted have the condition as a result of a de novo disease-causing variant. In this case series, we present 8 pediatric patients at Mother Teresa University Hospital Center in Tirana, Albania whose genetic diagnosis was confirmed by Whole exome sequencing including Next-generation sequencing-based Copy number variation analysis. Based on our clinical findings, they all meet the revised clinical diagnostic criteria of Neurofibromatosis type I by the International Consensus Conference held in 2021. In 5 of them, the variant was inherited from one of the parents, while in the remaining 3 the variant was de novo. Herein we discuss each genotype detected, the coordinates, class, and the modifications they induce in the neurofibromin protein. We also discuss our patients’ phenotypes; the cases of two pairs of siblings with identical inherited variants but with different clinical manifestations caught our interest, but studies confirm that the phenotype varies even among individuals with identical variants. In the end, identifying the signs and symptoms early and with certainty and rapidly assigning the cases to qualified healthcare professionals is important for patients with neurofibromatosis type I.},
 year = {2023}
}

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TY  - JOUR
T1  - Case Series: Neurofibromatosis Type 1 in 8 Pediatric Patients; Genotype and Phenotype Analysis
AU  - Afërdita Tako Kumaraku
AU  - Kristi Aleksi
AU  - Aida Bushati
AU  - Armand Shehu
AU  - Blerina Saraçi
AU  - Renald Meçani
AU  - Paskal Cullufi
Y1  - 2023/05/17
PY  - 2023
N1  - https://doi.org/10.11648/j.ijmcr.20230202.11
DO  - 10.11648/j.ijmcr.20230202.11
T2  - International Journal of Medical Case Reports
JF  - International Journal of Medical Case Reports
JO  - International Journal of Medical Case Reports
SP  - 8
EP  - 11
PB  - Science Publishing Group
SN  - 2994-7049
UR  - https://doi.org/10.11648/j.ijmcr.20230202.11
AB  - Neurofibromatosis type I is a multi-systemic disorder caused by variants in the neurofibromin, a gene on chromosome 17 that regulates a variety of cellular functions important for tumorigenesis. Clinically it is characterized by multiple café-au-lait spots, intertriginous freckling, neurofibromas, and learning disability or behavior problems. Neurofibromatosis type I is inherited in an autosomal dominant manner, but approximately half of those afflicted have the condition as a result of a de novo disease-causing variant. In this case series, we present 8 pediatric patients at Mother Teresa University Hospital Center in Tirana, Albania whose genetic diagnosis was confirmed by Whole exome sequencing including Next-generation sequencing-based Copy number variation analysis. Based on our clinical findings, they all meet the revised clinical diagnostic criteria of Neurofibromatosis type I by the International Consensus Conference held in 2021. In 5 of them, the variant was inherited from one of the parents, while in the remaining 3 the variant was de novo. Herein we discuss each genotype detected, the coordinates, class, and the modifications they induce in the neurofibromin protein. We also discuss our patients’ phenotypes; the cases of two pairs of siblings with identical inherited variants but with different clinical manifestations caught our interest, but studies confirm that the phenotype varies even among individuals with identical variants. In the end, identifying the signs and symptoms early and with certainty and rapidly assigning the cases to qualified healthcare professionals is important for patients with neurofibromatosis type I.
VL  - 2
IS  - 2
ER  -

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