Neurofibromatosis Type 1 (NF1) is a common genetic disorder of childhood, characterized by highly variable expressivity. In addition to café-au-lait spots, it shows multisystemic involvement and may cause skeletal abnormalities, tumor predisposition, and neurodevelopmental delay during childhood. This study aims to investigate the clinical and molecular characteristics of pediatric NF1 patients and to explore possible genotype–phenotype correlations. This study retrospectively evaluated the clinical and molecular findings of 148 pediatric NF1 patients, identifying genotype–phenotype correlations through Next-Generation Sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) analysis. The mean age at diagnosis was 8.7 years (1 month to 17 years), with a male-to-female ratio of 0.8. Cafe-au-lait spots were the most common finding (99.3%), followed by freckling (46.6%) and Lisch nodules (28.4%). Additional findings included short stature (29.3%), scoliosis (11.4%), neurodevelopmental delay (14.9%), cutaneous neurofibromas (6.8%), plexiform neurofibromas (6.8%), and optic pathway gliomas (6.7%). Magnetic Resonance Imaging revealed T2 hyperintensities in 72.6% of cases. NGS identified NF1 variants in 94.5% of patients, and MLPA detected full-gene deletions in 2 additional cases. With a molecular diagnostic yield of 95.9%, this study identifies 14 novel variants.Conclusion: This study expands the NF1 variant spectrum in children and emphasizes the value of molecular testing for early diagnosis, especially in infants and those with atypical features. Age-stratified clinical data from a large pediatric cohort revealed a potential link between truncating variants and axillary/inguinal freckling. Beyond diagnosis, molecular testing also supports surveillance and genetic counseling, highlighting its clinical utility in managing pediatric NF1.<Table Float="No" ID="Taba"> <tgroup cols="1"> <colspec align="left" colname="c1" colnum="1" /> <tbody> <row> <entry align="left" colname="c1"> What is Known: • NF1 is a well-known genetic disorder with highly variable expressivity. It shows a wide range of clinical findings, even among patients with the same genetic variant. While some specific genotype–phenotype links have been reported, most NF1 variants do not show clear clinical patterns. Certain features, like café-au-lait macules, appear early in infancy, but others, such as freckling or neurofibromas, often appear later. </entry> </row> <row> <entry align="left" colname="c1"> What is New: • In our pediatric NF1 cohort, axillary/inguinal freckling was found to be significantly more common in patients with truncating variants. For Lisch nodules, cutaneous neurofibromas, tumor presence, and especially T2 hyperintensities, point estimates suggested a non-significant trend toward higher frequencies in the truncating group. This suggests that some features may differ depending on the type of mutation. A total of 14 novel variants in NF1 were identified through NGS. </entry> </row> </tbody> </tgroup> </Table>

Clinical and molecular characterization of 148 pediatric neurofibromatosis type 1 patients: a single-center study identifying 14 novel variants

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发表日期：

2025年11月12日

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Aslı Genç,
Yasemin Ünal,
Ahmet Cevdet Ceylan,
Mustafa Altan,
Esra Gürkaş,
Derya Özyörük,
Esra Kılıç

摘要

Neurofibromatosis Type 1 (NF1) is a common genetic disorder of childhood, characterized by highly variable expressivity. In addition to café-au-lait spots, it shows multisystemic involvement and may cause skeletal abnormalities, tumor predisposition, and neurodevelopmental delay during childhood. This study aims to investigate the clinical and molecular characteristics of pediatric NF1 patients and to explore possible genotype–phenotype correlations. This study retrospectively evaluated the clinical and molecular findings of 148 pediatric NF1 patients, identifying genotype–phenotype correlations through Next-Generation Sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) analysis. The mean age at diagnosis was 8.7 years (1 month to 17 years), with a male-to-female ratio of 0.8. Cafe-au-lait spots were the most common finding (99.3%), followed by freckling (46.6%) and Lisch nodules (28.4%). Additional findings included short stature (29.3%), scoliosis (11.4%), neurodevelopmental delay (14.9%), cutaneous neurofibromas (6.8%), plexiform neurofibromas (6.8%), and optic pathway gliomas (6.7%). Magnetic Resonance Imaging revealed T2 hyperintensities in 72.6% of cases. NGS identified NF1 variants in 94.5% of patients, and MLPA detected full-gene deletions in 2 additional cases. With a molecular diagnostic yield of 95.9%, this study identifies 14 novel variants.

Conclusion: This study expands the NF1 variant spectrum in children and emphasizes the value of molecular testing for early diagnosis, especially in infants and those with atypical features. Age-stratified clinical data from a large pediatric cohort revealed a potential link between truncating variants and axillary/inguinal freckling. Beyond diagnosis, molecular testing also supports surveillance and genetic counseling, highlighting its clinical utility in managing pediatric NF1.

What is Known:

• NF1 is a well-known genetic disorder with highly variable expressivity. It shows a wide range of clinical findings, even among patients with the same genetic variant. While some specific genotype–phenotype links have been reported, most NF1 variants do not show clear clinical patterns. Certain features, like café-au-lait macules, appear early in infancy, but others, such as freckling or neurofibromas, often appear later.

What is New:

• In our pediatric NF1 cohort, axillary/inguinal freckling was found to be significantly more common in patients with truncating variants. For Lisch nodules, cutaneous neurofibromas, tumor presence, and especially T2 hyperintensities, point estimates suggested a non-significant trend toward higher frequencies in the truncating group. This suggests that some features may differ depending on the type of mutation. A total of 14 novel variants in NF1 were identified through NGS.