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

Area of Science:

• Genetics
• Pediatrics
• Rare Diseases

Background:

• Neurofibromatosis type 1 (NF1) is a genetic disorder with diverse symptoms.
• Genotype-phenotype correlations in NF1 are not fully understood, especially in diverse populations.
• Limited data exists on NF1 in underrepresented South American populations.

Purpose of the Study:

• To investigate genotype-phenotype correlations in pediatric NF1 patients from Ecuador.
• To identify novel pathogenic variants and characterize clinical manifestations in this cohort.
• To explore the role of ancestry in NF1 presentation.

Main Methods:

• Clinical evaluation of three pediatric patients with suspected NF1.
• Next-generation sequencing (NGS) using the TruSight Cancer panel.
• Ancestry analysis using insertion-deletion (InDel) markers and variant classification via ACMG/AMP guidelines.

Main Results:

• Identified three distinct pathogenic NF1 variants: one nonsense (p.Arg1534Ter) and two missense (p.Gln20His, p.Asp1644Asn).
• Observed clinical features including early orbital plexiform neurofibroma, café-au-lait macules, freckling, radial bone dysplasia, and prepubertal gynecomastia.
• All patients showed predominantly Native American ancestry, and early pigmentary signs were key diagnostic indicators.

Conclusions:

• This case series expands the known NF1 mutational and phenotypic spectrum in Ecuadorian children.
• Early pigmentary signs are crucial diagnostic indicators, alongside less common manifestations like radial bone dysplasia and prepubertal gynecomastia.
• Integrating molecular diagnostics with clinical evaluation can lead to earlier, precise NF1 diagnosis and personalized management.