Linear and whorled hypermelanosis: A multicentre retrospective cohort of 33 patients

Linear and whorled nevoid hypermelanosis (LWNH) is a rare form of pigmentary mosaicism characterized by streaky, linear or whorled hyperpigmented macules distributed along Blaschko's lines, without preceding inflammation or atrophy.1 To date, approximately 60 cases have been reported.2 Extracutaneous manifestations—most commonly neurological, musculoskeletal, ophthalmological and cardiac—have been described in 15–40% of patients.2 LWNH is most frequently attributed to chromosomal mosaicism3 and has also been associated with pathogenic variants (PVs) in KITLG4 and TP63.5 We conducted a multicentre retrospective cohort study across seven French university dermatology departments to refine the clinical spectrum of LWNH, estimate the prevalence of extracutaneous manifestations, and explore genotype–phenotype correlations. Photographic archives were screened using the keywords ‘hyperpigmentation’, ‘mosaicism’ and ‘linear’. LWNH was defined according to Kalter's criteria.1 Patients with associated linear hypopigmented lesions or phylloid hypermelanosis6 were excluded. Borderline cases were independently reviewed by two experts, and those without consensus were excluded. Medical records and clinical photographs were reviewed using a standardized classification of genetic mosaicism.7 When available, histopathology was reviewed to support the diagnosis according to Kalter's criteria. From 2000 to 2025, 33 patients were identified, with a female-to-male ratio of 1.4:1 (Table 1). Median age at onset was under 1 year (range, 0–1), and the median diagnostic delay was 2 years (range, 0–9). The most frequent cutaneous presentation consisted of narrow bands following Blaschko's lines (pattern B4), observed in 79% of patients. Skin involvement was bilateral in 55% of cases and extensive (F4) in 45% (Figure 1a–h). Whole genome sequencing or exome, n positive results/n test NGS panelb, n positive results/n test 2/5 3/10 Extracutaneous abnormalities were present in 61% of patients. Neurological manifestations were the most common (52%), followed by craniofacial morphological abnormalities (21%), skeletal anomalies (21%), ophthalmological involvement (18%) and cardiac abnormalities (12%). Cytogenetic and/or molecular testing of lesional skin and/or blood was performed in 42% of patients. A genetic abnormality definitively associated with the pigmentary phenotype was identified in 30% of tested individuals. Identified abnormalities included chromosomal mosaicism—triploidy and mosaic trisomy 14—in three patients; mosaic KITLG PVs in three patients [p.(Val37Gly), p.(Asp110Asn) and p.(Asp110Val)]; and one germline MECP2 PV (exon 4 deletion). No significant association (Pearson's chi-squared test) was observed between cutaneous extent (F1–F4) or mosaic pattern (B1–B7) and either the presence of extracutaneous manifestations or the likelihood of identifying a genetic abnormality (Figure 1a). Notably, all KITLG-positive patients shared a similar cutaneous phenotype characterized by facial involvement and absence of severe extracutaneous features (Figure 1b–d). The patient carrying the MECP2 PV presented with hypotonia, Lennox–Gastaut syndrome and global developmental delay, along with scoliosis and osteoporosis. To the best of our knowledge, this is the largest LWNH cohort reported to date. We confirmed a balanced sex ratio, infantile onset and predominance of the B4/F4 pattern. The frequency and spectrum of extracutaneous manifestations were largely consistent with previous reports.1-3, 8 Compared with literature, neurological involvement was more frequent (59% vs 29%), whereas facial and osteoarticular abnormalities were less common (both 21% vs 56%), possibly reflecting recruitment bias through collaborations with neuropaediatricians in tertiary referral centres. Chromosomal mosaicism rates were comparable to those previously reported.8 The low testing rate (42%) likely reflects historical cases, retrospective design and limited access to consent for molecular testing, especially affected skin sampling in isolated cutaneous disease. Our three KITLG-positive cases extend prior observations based on a single report.4 Two patients carried substitutions at the recurrent Asp110 residue, and together with p.(Val37Gly), these findings support a shared KIT-binding domain mechanism consistent with postzygotic mosaic familial progressive hyper- and hypopigmentation/LWNH.9 Although based on a small number of cases, the combination of facial involvement and absence of severe extracutaneous manifestations in KITLG-positive patients may suggest a recognizable pattern and could prompt targeted KITLG testing. In patients with mosaic trisomy 14, we confirmed a distinctive pattern of reticulate hyperpigmentation involving the dorsal hands and anterior thighs.10 We describe LWNH in association with a germline MECP2 PV. Given the X-linked location of MECP2, skewed X-chromosome inactivation may lead to functional mosaicism and Blaschko-linear pigmentation, as previously reported with USP9X (MIM#300968) and DDX3X (MIM#300958). This represents only the second reported LWNH case associated with a non-mosaic PV, suggesting that LWNH is not restricted to somatic mosaic causes. Given the broad clinical and molecular spectrum of LWNH, comprehensive evaluation—including molecular testing of both lesional skin and blood—is warranted. We thank the patients who participated in the study and their parents. This work was supported as part of the national plan for rare diseases by the French Ministry of Health. The authors declare no conflicts of interest. This retrospective multicentre study received a favourable opinion from the University of Montpellier Research Ethics Committee (Comité d'Éthique de la Recherche) (consultative opinion no. UM 2025-086bis; 25 November 2025). Data extraction and analysis were performed after ethics approval. The patients or their parents/guardians in this manuscript have given written informed consent for publication of their case details and clinical photographs/images. This retrospective multicentre study received a favourable opinion from the University of Montpellier Research Ethics Committee (Comité d'Éthique de la Recherche) (consultative opinion no. UM 2025-086bis; 25 November 2025). Data extraction and analysis were performed after ethics approval. The data that support the findings are available from the corresponding author upon reasonable request.