Solar urticaria involves rapid mast cell STAT3 activation and neutrophil recruitment, with FcεRI as an upstream regulator.

BACKGROUND: Solar urticaria is a rare photodermatosis characterized by rapid-onset sunlight-induced urticaria, but its pathophysiology is not well understood. OBJECTIVE: We sought to define cutaneous cellular and molecular events in the evolution of solar urticaria following its initiation by solar-simulated UV radiation (SSR) and compare with healthy controls (HC). METHODS: Cutaneous biopsy specimens were taken from unexposed skin and skin exposed to a single low (physiologic) dose of SSR at 30 minutes, 3 hours, and 24 hours after exposure in 6 patients with solar urticaria and 6 HC. Biopsy specimens were assessed by immunohistochemistry and bulk RNA-sequencing analysis. RESULTS: In solar urticaria specimens, there was enrichment of several innate immune pathways, with striking early involvement of neutrophils, which was not observed in HC. Multiple proinflammatory cytokine and chemokine genes were upregulated (including IL20, IL6, and CXCL8) or identified as upstream regulators (including TNF, IL-1ß, and IFN-γ). IgE and FcεRI were identified as upstream regulators, and phosphorylated signal transducer and activator of transcription 3 expression in mast cells was increased in solar urticaria at 30 minutes and 3 hours after SSR exposure, suggesting a mechanism of mast cell activation. Clinical resolution of solar urticaria by 24 hours mirrored resolution of inflammatory gene signature profiles. Comparison with available datasets of chronic spontaneous urticaria showed transcriptomic similarities relating to immune activation, but several transcripts were identified solely in solar urticaria, including CXCL8 and CSF2/3. CONCLUSIONS: Solar urticaria is characterized by rapid signal transducer and activator of transcription 3 activation in mast cells and involvement of multiple chemotactic and innate inflammatory pathways, with FcεRI engagement indicated as an early event.

Oculo-auriculo-vertebral spectrum: clinical and molecular analysis of 51 patients.

INTRODUCTION: Oculo-auriculo-vertebral spectrum (OAVS OMIM 164210) is a craniofacial developmental disorder affecting the development of the structures derived from the 1st and the 2nd branchial arches during embryogenesis, with consequential maxillary, mandibular, and ear abnormalities. The phenotype in OAVS is variable and associated clinical features can involve the cardiac, renal, skeletal, and central nervous systems. Its aetiology is still poorly understood. METHODS: We have evaluated the clinical phenotypes of 51 previously unpublished patients with OAVS and their parents, and performed comparative genomic hybridization microarray studies to identify potential causative loci. RESULTS: Of all 51 patients, 16 (31%) had a family history of OAVS. Most had no relevant pre-natal history and only 5 (10%) cases had a history of environmental exposures that have previously been described as risk factors for OAVS. In 28 (55%) cases, the malformations were unilateral. When the involvement was bilateral, it was asymmetric. Ear abnormalities were present in 47 (92%) patients (unilateral in 24; and bilateral in 23). Hearing loss was common (85%), mostly conductive, but also sensorineural, or a combination of both. Hemifacial microsomia was present in 46 (90%) patients (17 also presented facial nerve palsy). Ocular anomalies were present in 15 (29%) patients. Vertebral anomalies were confirmed in 10 (20%) cases; 50% of those had additional heart, brain and/or other organ abnormalities. Brain abnormalities were present in 5 (10%) patients; developmental delay was more common among these patients. Limb abnormalities were found in 6 (12%) patients, and urogenital anomalies in 5 (10%). Array-CGH analysis identified 22q11 dosage anomalies in 10 out of 22 index cases screened. DISCUSSION: In this study we carried out in-depth phenotyping of OAVS in a large, multicentre cohort. Clinical characteristics are in line with those reported previously, however, we observed a higher incidence of hemifacial microsomia and lower incidence of ocular anomalies. Furthermore our data suggests that OAVS patients with vertebral anomalies or congenital heart defects have a higher frequency of additional brain, limb or other malformations. We had a higher rate of familial cases in our cohort in comparison with previous reports, possibly because these cases were referred preferentially to our genetic clinic where family members underwent examination. We propose that familial OAVS cases show phenotypic variability, hence, affected relatives might have been misclassified in previous reports. Moreover, in view of its phenotypic variability, OAVS is potentially a spectrum of conditions, which overlap with other conditions, such as mandibulofacial dysostosis. Array CGH in our cohort identified recurrent dosage anomalies on 22q11, which may contribute to, or increase the risk of OAVS. We hypothesize that although the 22q11 locus may harbour gene(s) or regulatory elements that play a role in the regulation of craniofacial symmetry and 1st and 2nd branchial arch development, OAVS is a heterogeneous condition and many cases have a multifactorial aetiology or are caused by mutations in as yet unidentified gene(s).