As reported in the European Medical Journal, new research suggests that cherry angiomas occur more frequently and at an earlier age in people with neurofibromatosis type 1 (NF1), raising the possibility that these common vascular skin lesions are part of the broader clinical spectrum of the genetic disorder.
In a prospective cross-sectional study, investigators evaluated 259 participants aged 15 years and older, including 102 individuals with confirmed NF1 and 157 control subjects. The study was performed at a French national referral centre specializing in neurofibromatosis and combined clinical assessment with detailed molecular and genomic investigations.
The researchers found a markedly higher prevalence of cherry angiomas among patients with NF1. Nearly half of those with the condition exhibited at least one cherry angioma, compared with fewer than one in five participants in the control group. The relationship remained significant after adjusting for demographic factors and in matched analytical models designed to reduce bias.
Statistical analysis further demonstrated a strong association between NF1 and the presence of cherry angiomas, with affected individuals showing more than four times the likelihood of developing these lesions compared with controls.
Genetic Evidence Supports a Biological Link
To explore the mechanisms underlying this association, the study team conducted molecular analyses of cherry angioma tissue obtained from participants with NF1 and from healthy individuals.
A key finding was the identification of somatic “second-hit” loss-of-function mutations in the NF1 gene within two-thirds of NF1-associated angiomas examined. These mutations were absent in angiomas collected from controls. The results support the concept of biallelic NF1 inactivation within the lesions, a process known to contribute to tumor development in NF1-associated conditions.
Additional genetic profiling revealed the presence of other activating mutations, including alterations involving the GNAQ gene, one of the most commonly detected coexisting variants. These findings suggest that multiple molecular events may contribute to lesion formation.
Endothelial Cells Appear Central to Lesion Development
Cell-specific sequencing provided further insight into the origin of these vascular growths. Investigators found that NF1 second-hit mutations were primarily located in endothelial cells and telocytes, with endothelial cells showing the highest mutation burden.
Laboratory analyses also demonstrated increased activation of extracellular signal-regulated kinase (ERK) signalling pathways in affected vascular cell populations. This observation is consistent with enhanced cellular signalling activity resulting from NF1 loss and provides additional mechanistic support for the development of cherry angiomas in this patient population.
Expanding the Clinical Spectrum of NF1
The authors propose that cherry angiomas may represent a previously underappreciated vascular manifestation of NF1. Traditionally, the disorder has been associated largely with abnormalities arising from neural crest-derived tissues, but these findings point toward a broader role for NF1 in vascular biology.
Although the study design cannot establish causality, the convergence of epidemiological, genetic, and cellular evidence suggests that the increased frequency of cherry angiomas in NF1 is unlikely to be a coincidental observation.
The researchers believe these lesions could serve as a useful model for studying NF1-related vascular disease and may help expand current understanding of the range of neoplastic and vascular manifestations associated with NF1.
