Neurofibromatosis Type 1 in Ecuador: genotype-phenotype correlations from a case series

Neurofibromatosis type 1 (NF1) is a multisystemic genetic disorder caused by pathogenic variants in the 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.

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.

Three distinct pathogenic 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. analyses predicted a pathogenic classification of all variants. Early pigmentary signs, present in all cases, served as key diagnostic indicators.

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.