Cherry Angiomas in Individuals With Neurofibromatosis Type 1.

Biallelic NF1 inactivation through a somatic second hit in the endothelial cells and telocytes of cherry angiomas, with RAS-MAPK pathway activation and co-occurring activating variants, most often in GNAQ.

This prospective, comparative, cross-sectional epidemiological study compared 102 individuals aged 15 years or older with confirmed neurofibromatosis type 1 with 157 controls at a French national referral centre between October 2020 and March 2021. Cherry angiomas were more frequent in affected individuals than in controls (48% vs 18%; odds ratio 4.26; 95% CI 2.44-7.56) and occurred at a younger age, an association that persisted after adjustment for age and sex and in propensity score-matched analyses. Somatic loss-of-function NF1 second hits were found in 26 of 39 angiomas from affected individuals (67%) and in none from controls, indicating biallelic NF1 inactivation. Genomic profiling showed frequent co-occurring activating variants, most commonly in GNAQ, and cell-specific sequencing localised the second hit mainly to endothelial cells and telocytes, with higher variant allele frequencies in endothelial cells and increased phospho-ERK signalling. The authors propose cherry angiomas as a frequent, previously unrecognised vascular manifestation of the disease.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The sign is easy to look for at the bedside, but its standalone diagnostic value is low: cherry angiomas are common in the general population and 18% of controls had them, so they cannot serve as a criterion on their own. The study is single-centre, cross-sectional and based on patients followed at a referral centre, which exposes it to referral bias; independent replication and longitudinal data would be needed before adding this sign to routine follow-up. The demonstration of a somatic NF1 second hit in endothelial cells is, by contrast, convincing and provides an accessible model for studying the vasculopathy of the disease.

Analysis by Dr Thibaut Benquey