Cherry Angiomas More Common in NF1, With Vascular-Cell Second Hits

Key Takeaways

• At a French referral center, cherry angiomas were found in 48% of participants with NF1 versus 18% of controls without NF1.
• Angiomas occurred at younger ages in the NF1 group, and the prevalence association persisted after age and sex adjustment and propensity-score matching.
• Sampled NF1-associated angiomas contained somatic NF1 second hits and frequently had co-occurring activating variants, most commonly involving GNAQ.
• NF1 second hits predominated in endothelial cells and telocytes, which also showed increased phospho-ERK staining.

Cherry angiomas are a familiar skin finding, but how often they occur in people with neurofibromatosis type 1 (NF1) relative to others remains uncertain. Whether these lesions reflect NF1-related vascular biology is a separate question: their appearance alone cannot establish what is happening within vascular cells. Investigators compared people with and without NF1 and examined angioma tissue to explore both questions.

At a French national neurofibromatosis referral center in Henri-Mondor University Hospital, Créteil, Fertitta and colleagues prospectively enrolled 259 participants, including 102 with confirmed NF1 and 157 controls without NF1, for their JAMA Dermatology study of cherry angiomas in NF1. This comparative cross-sectional study enrolled people aged 15 years or older between October 2020 and March 2021. Investigators compared angioma prevalence and subsequently analyzed consented angiomas from people with NF1 and healthy volunteers using histopathology, genomic profiling, cell-specific sequencing, and immunofluorescence.

Cherry angiomas were more prevalent among participants with NF1 than among controls; the reported odds ratio was 4.26 (95% confidence interval 2.44-7.56). Angiomas also occurred at younger ages in the NF1 group. The prevalence association persisted after adjustment for age and sex and in propensity-score-matched analyses; the reported odds ratio is not identified as an adjusted or matched estimate.

Among sampled NF1-associated cherry angiomas, 26 of 39 (67%) carried somatic NF1 loss-of-function second hits, indicating biallelic inactivation; no sampled control lesions had such hits. Genomic profiling identified frequent co-occurring activating variants, most commonly involving GNAQ. Cell-specific sequencing localized NF1 second hits predominantly to endothelial cells and telocytes. Immunofluorescence showed increased phosphorylated extracellular signal-regulated kinase (phospho-ERK) staining in those cell populations.

The single French referral-center setting limits how broadly the prevalence comparison can be generalized, and the cross-sectional design cannot establish that NF1 caused the angiomas. Although tissue analyses characterized lesions, they did not establish whether angiomas can identify NF1, predict later vascular outcomes, or change the effects of screening or treatment.

The investigators propose that the greater frequency of cherry angiomas in people with NF1, together with biallelic NF1 inactivation in vascular cells, supports a possible NF1 vascular phenotype. They suggest these lesions as a model for studying NF1-related vasculopathy.

Clinician Questions

How did participant ages differ between the NF1 and control groups evaluated for cherry angiomas?

Median participant age was 34 years among people with confirmed NF1 and 40 years among controls without NF1. These were ages at enrollment, not ages when cherry angiomas first appeared; numerical ages at angioma occurrence were not established in the available findings.

Which cells had higher NF1 variant allele frequencies in NF1-associated cherry angiomas?

In angiomas sampled from people with NF1, cell-specific sequencing found higher NF1 variant allele frequencies in endothelial cells than in telocytes. The relative finding does not mean second hits were confined to endothelial cells.