<scp>ILVEN</scp> revisited: A mosaic spectrum rather than a single disease

We read with great interest the review article by Aghajani Marra et al.1 They make a compelling case that ILVEN is not a single entity at all, but rather a broad group of mosaic inflammatory conditions that are visibly similar. This shift, from treating ILVEN as a single patterned naevus to viewing it as a genetically diverse group of disorders, has major implications for how we diagnose and manage these patients going forward.1, 2 One of the main points the authors make is that relying solely on clinical presentation or histology is no longer sufficient. They outline six key genes (CARD14, NSDHL, PMVK, KRT10, GJA1, and ABCA12) where somatic variants in lesional skin can each produce ILVEN-like lesions, but with different underlying mechanisms and very different treatment responses.1-4 The examples they provide, such as CARD14-driven disease responding to IL-17 or IL-23 inhibitors or NSDHL-related lesions improving with topical statin/cholesterol therapies, really highlight how gene-based analysis can outperform pattern-based diagnosis.1-3, 5 At the same time, the authors acknowledge that our current understanding is incomplete. Even with deep sequencing, about 60% of patients still have no identifiable pathogenic variant.1 So while the field is clearly moving toward genotype-driven therapy, current evidence is limited to case reports.1-3 The discussion around re-classifying some ILVEN-like cases, such as PMVK or NSDHL mutations being more consistent with porokeratosis or CHILD-spectrum disorders, is particularly interesting.1, 2 This not only affects treatment choices but also restructures how we describe and categorize these conditions. Similarly, the suggestion that HRAS-associated cases might eventually benefit from MEK inhibitors hints toward the possibility that targeted therapies will become the norm.1, 6 A question raised by the review is when to pursue genetic testing. While universal genotyping is ideal, the authors point out the very real barriers of cost, access and limited support.1 Their suggestion is to use a pragmatic approach, starting with targeted therapies based on clinical suspicion, and reserving sequencing for atypical cases.1 This seems reasonable in limited resource settings but we would argue that a mosaic panel on DNA extracted from lesional skin as performed by the Genomic Medicine Service in the UK with deep sequencing to identify low-level somatic variants is best practice.3 It is also important for genetic counselling, prenatal diagnosis and identification of associated extracutaneous disorders.3, 4 In patients with Mosaic RASopathies, the association with cancer and implications for cancer screening are important.6 Going forward, the review highlights several gaps that need to be addressed—the need for larger registries to map genotype–phenotype relationships and better integration of genomic testing into Dermatology without increasing disparities in care.1 More research is also required to identify new genes causing ILVEN.1 While these are ambitious goals, they align with the trajectory of genomic and precision medicine. Overall, this review presents a consolidation of emerging evidence and a call for dermatologists to rethink longstanding practices. The disease entity of ILVEN is less about what we see in clinic or at our dermatopathology meetings and more about the molecular network driving the disease.1-3 EAOT declares consultancy for Palvella Therapeutics, Azitra and Kamari Pharma, clinical trials with Palvella Therapeutics and Kamari Pharma, funding from Unilever and the Leo Foundation. She is a speaker for Almirall (all money goes to University or Hospital). No conflicts relevant to this commentary. RM has no conflict of interest to disclose. Data sharing is not applicable to this article as no new data were created or analysed in this study.