TOPLINE

Cherry angiomas (CAs) were common in individuals with neurofibromatosis type 1 (NF1) compared with control individuals without NF1. Biallelic NF1 inactivation in endothelial cells and telocytes supported CAs as a vascular manifestation of NF1.

METHODOLOGY

• Researchers conducted a prospective study at Henri-Mondor University Hospital from October 2020 to March 2021 to assess the prevalence of CAs in patients with NF1 and the underlying cellular and genetic mechanisms driving their development.
• The study included 259 participants aged 15 years or older: 102 individuals with confirmed NF1 (median age, 36.4 years) and 157 control individuals without NF1 selected from the dermatology emergency clinic (median age, 44.2 years). CAs were defined as red or purple papules ≤ 1cm; patients with NF1 were graded by disease severity (minor to severe or at-risk).
• A single specialist examined NF1 patients, while general dermatologists examined control individuals.
• CA samples underwent microscopic staining (to detect Schwann cells) and staged genetic sequencing: NF1-targeted next-generation sequencing (39 lesions/23 patients), a 23-gene overgrowth NGS panel (6 lesions), and a broader 571-gene panel (17 lesions/15 patients).
• Researchers isolated specific vascular cell subpopulations (endothelial cells, telocytes, and pericytes) from six lesions in two patients and individually sequenced to determine somatic NF1 second hits. Fluorescent staining (including phospho-extracellular signal-regulated kinase [ERK], a marker of the RAS-mitogen-activated protein kinase growth pathway, was done on three CAs and three normal skin biopsy specimens.

TAKEAWAY

• CAs were more frequent in individuals with NF1 than in control individuals (48% vs 18%; adjusted odds ratio [OR], 10.79, 95% CI, 5.25-23.92).
• Somatic NF1 loss-of-function second hits were identified in 26 of 39 NF1-associated CAs (67%), with none in control individuals, indicating an association between biallelic NF1 inactivation and NF1-associated CAs.
• Comprehensive genomic profiling revealed frequent co-occurring activating variants in 12 of 17 lesions (71%), most commonly GNAQ codon 209 oncogenic variants in 5 of 17 lesions (29%), with comparable variant allele frequencies suggesting a shared cellular origin. Ultraviolet (UV)-related single-base substitution and double-base substitution in 12 of 17 lesions (71%) suggested frequent UV-related mutagenesis in NF1-associated CAs.
• Cell-specific sequencing demonstrated that NF1 second hits arose predominantly in endothelial cells (detected in five of six CAs) and telocytes (detected in four of six CAs), with higher variant allele frequencies in endothelial cells, while immunofluorescence showed increased phospho-ERK signaling in these vascular cell populations.

IN PRACTICE

The results of the study “suggest that CAs represent a previously unrecognized vascular manifestation of NF1 that is associated with biallelic NF1 inactivation and frequently cooperating with G-alpha-q pathway variants,” the authors of the study wrote. By identifying endothelial cells and telocytes as the key cellular compartments undergoing NF1 loss, they noted, the study uncovered a new model of vascular tumorigenesis in NF1. “These observations,” they added, “suggest that other NF1-associated vasculopathies may share a similar pathogenic basis.”

SOURCE

The study was led by Laura Fertitta, MD, Service de Dermatologie, Hôpital Henri-Mondor, Assistance Publique-Hôpitaux de Paris, Paris Est Créteil University, Créteil, France, and was published online on August 19 in JAMA Dermatology.

LIMITATIONS

Different clinicians examined NF1 and control groups, potentially introducing classification bias. Low tumor cellularity and technical limitations could have prevented detection of some NF1 second hits. GNA14 was not included in the comprehensive genomic profiling panel. UV exposure was not quantified.

DISCLOSURES

The study was funded by the Neurofibromatosis Therapeutic Acceleration Program. Fertitta and other authors disclosed receiving consulting fees, personal fees, and grants from Alexion Pharmaceuticals, Pfizer, and several organizations outside the submitted work. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.