Café-au-lait macules (CALMs) constitute a major diagnostic criterion for neurofibromatosis type 1 (NF1), yet infants presenting exclusively with CALMs often do not fulfill full diagnostic criteria in early life. This retrospective cohort study aimed to quantify longitudinal changes in CALM burden during the first two years of life in children with NF1 and to assess the relevance of early lesion number for subsequent diagnostic threshold fulfillment. Sixty-three children with NF1 who initially presented with typical multiple CALMs were included. CALM counts were documented at 6, 12, and 24 months using standardized digital photography. CALM counts increased significantly over time (χ2(2) = 124.097, p < 0.001; Kendall’s W = 0.985), rising from a mean of 5.86 ± 2.63 at 6 months to 17.49 ± 7.75 at 24 months. While 38.1% of infants met the six-lesion diagnostic threshold (≥ 6 CALMs) at 6 months, 96.8% did so by 24 months, and 94.5% of those initially below the diagnostic threshold (< 6 CALMs) met the diagnostic threshold during follow-up by 24 months. Conclusion: CALM burden increases markedly during the first two years of life in children with NF1. By 24 months, nearly all children met the CALM-based diagnostic threshold (≥ 6 CALMs), indicating that this period represents a critical window for diagnostic threshold fulfillment. These findings support a time-dependent framework for the evaluation and follow-up of infants presenting with isolated multiple CALMs. <Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry nameend="c2" namest="c1"> What is Known: • Multiple café-au-lait macules (CALMs) are a major diagnostic criterion for neurofibromatosis type 1 (NF1), with additional features often emerging later in childhood. • Infants presenting exclusively with CALMs frequently require longitudinal follow-up before diagnosis can be established. </entry> </row> <row> <entry nameend="c2" namest="c1"> What is New: • Quantitative data on early longitudinal CALM progression in NF1 are limited. • This study demonstrates a marked increase in CALM burden during the first two years of life, with nearly all children meeting the diagnostic threshold by 24 months. </entry> </row> </tbody> </tgroup> </Table>

Early quantitative progression of café-au-lait macules and diagnostic threshold fulfilment by 24 months in neurofibromatosis type 1

期刊论文
发表日期：

2026年5月22日

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Alexios Alexopoulos,
Dimitrios Ntokos,
Louiza Kontara,
Michael Miligkos,
Maria Dakoutrou,
Pavlos Sarafis,
Christina Kanaka-Gantenbein,
Lamprini Nasi

摘要

Café-au-lait macules (CALMs) constitute a major diagnostic criterion for neurofibromatosis type 1 (NF1), yet infants presenting exclusively with CALMs often do not fulfill full diagnostic criteria in early life. This retrospective cohort study aimed to quantify longitudinal changes in CALM burden during the first two years of life in children with NF1 and to assess the relevance of early lesion number for subsequent diagnostic threshold fulfillment. Sixty-three children with NF1 who initially presented with typical multiple CALMs were included. CALM counts were documented at 6, 12, and 24 months using standardized digital photography. CALM counts increased significantly over time (χ²(2) = 124.097, p < 0.001; Kendall’s W = 0.985), rising from a mean of 5.86 ± 2.63 at 6 months to 17.49 ± 7.75 at 24 months. While 38.1% of infants met the six-lesion diagnostic threshold (≥ 6 CALMs) at 6 months, 96.8% did so by 24 months, and 94.5% of those initially below the diagnostic threshold (< 6 CALMs) met the diagnostic threshold during follow-up by 24 months. Conclusion: CALM burden increases markedly during the first two years of life in children with NF1. By 24 months, nearly all children met the CALM-based diagnostic threshold (≥ 6 CALMs), indicating that this period represents a critical window for diagnostic threshold fulfillment. These findings support a time-dependent framework for the evaluation and follow-up of infants presenting with isolated multiple CALMs.

What is Known:

• Multiple café-au-lait macules (CALMs) are a major diagnostic criterion for neurofibromatosis type 1 (NF1), with additional features often emerging later in childhood.

• Infants presenting exclusively with CALMs frequently require longitudinal follow-up before diagnosis can be established.

What is New:

• Quantitative data on early longitudinal CALM progression in NF1 are limited.

• This study demonstrates a marked increase in CALM burden during the first two years of life, with nearly all children meeting the diagnostic threshold by 24 months.