Neurofibromatosis Type 1 in Ecuador: genotype-phenotype correlations from a case series
Journal
Medwave
ISSN
0717-6384
Date Issued
2026-01-14
Author(s)
Elius Paz-Cruz
Patricia Guevara-Ramirez
Arianne Llamos Paneque
Emily Onofre
Christian Rivas Iglesias
Santiago Cadena-Ullauri
Rafael Tamayo-Trujillo
Viviana A. Ruiz-Pozo
Daniel Simancas-Racines
Abstract
INTRODUCTION
Neurofibromatosis type 1 (NF1) is a multisystemic genetic disorder caused by pathogenic variants in the NF1 gene, characterized by variable clinical manifestations such as pigmentary abnormalities, neurofibromas, skeletal dysplasia, and tumor predisposition. However, genotype-phenotype correlations remain insufficiently explored, particularly in underrepresented populations.
METHODS
Three unrelated Ecuadorian pediatric patients with a presumptive diagnosis of NF1 underwent detailed clinical evaluation, next-generation sequencing (NGS), using the TruSight Cancer panel, and ancestry analysis based on 46 ancestry-informative insertion-deletion (InDel) markers. Variants were classified according to ACMG/AMP guidelines using the Franklin and Variant Interpreter platforms, which incorporate in silico prediction tools to assess variant pathogenicity. RESULTS Three distinct pathogenic NF1 variants were identified: one nonsense (p.Arg1534Ter) and two missense (p.Gln20His, p.Asp1644Asn).
Clinical findings included early-onset orbital plexiform neurofibroma, multiple café-au-lait macules, axillary/inguinal freckling, radial bone dysplasia, cutaneous neurofibromas, and prepubertal gynecomastia. All patients exhibited predominantly Native American ancestry. In silico analyses predicted a pathogenic classification of all variants. Early pigmentary signs, present in all cases, served as key diagnostic indicators.
CONCLUSIONS
This case series expands the mutational and phenotypic spectrum of NF1 in a pediatric Ecuadorian cohort. Findings underscore the diagnostic value of early pigmentary signs and highlight less commonly reported manifestations such as radial bone dysplasia and prepubertal gynecomastia. Integrating molecular diagnostics with early clinical evaluation may enable earlier and more precise diagnosis, guiding personalized management strategies. Further studies should investigate genotype-phenotype correlations and the influence of ancestry on NF1 expression.
Neurofibromatosis type 1 (NF1) is a multisystemic genetic disorder caused by pathogenic variants in the NF1 gene, characterized by variable clinical manifestations such as pigmentary abnormalities, neurofibromas, skeletal dysplasia, and tumor predisposition. However, genotype-phenotype correlations remain insufficiently explored, particularly in underrepresented populations.
METHODS
Three unrelated Ecuadorian pediatric patients with a presumptive diagnosis of NF1 underwent detailed clinical evaluation, next-generation sequencing (NGS), using the TruSight Cancer panel, and ancestry analysis based on 46 ancestry-informative insertion-deletion (InDel) markers. Variants were classified according to ACMG/AMP guidelines using the Franklin and Variant Interpreter platforms, which incorporate in silico prediction tools to assess variant pathogenicity. RESULTS Three distinct pathogenic NF1 variants were identified: one nonsense (p.Arg1534Ter) and two missense (p.Gln20His, p.Asp1644Asn).
Clinical findings included early-onset orbital plexiform neurofibroma, multiple café-au-lait macules, axillary/inguinal freckling, radial bone dysplasia, cutaneous neurofibromas, and prepubertal gynecomastia. All patients exhibited predominantly Native American ancestry. In silico analyses predicted a pathogenic classification of all variants. Early pigmentary signs, present in all cases, served as key diagnostic indicators.
CONCLUSIONS
This case series expands the mutational and phenotypic spectrum of NF1 in a pediatric Ecuadorian cohort. Findings underscore the diagnostic value of early pigmentary signs and highlight less commonly reported manifestations such as radial bone dysplasia and prepubertal gynecomastia. Integrating molecular diagnostics with early clinical evaluation may enable earlier and more precise diagnosis, guiding personalized management strategies. Further studies should investigate genotype-phenotype correlations and the influence of ancestry on NF1 expression.