STIM1 and ORAI1 mutations leading to tubular aggregate myopathies are sensitive to the Store-operated Ca2+-entry modulators CIC-37 and CIC-39.

Gain-of-function mutations on STIM1 and ORAI1 genes are responsible for an increased store-operated calcium entry, and underlie the characteristic symptoms of three overlapping ultra-rare genetic disorders (i.e tubular aggregate myopathy, Stormorken syndrome, York platelet syndrome) that can be grouped as tubular aggregate myopathies. These mutations lead to a wide spectrum of defects, which usually include muscle weakness and cramps. Negative modulators of store-operated Ca2+-entry targeting wild-type STIM1 and ORAI1 have entered clinical trials for a different array of disorders, including pancreatitis, COVID-19, cancer, and autoimmune disorders and, while efficacy data is awaited, safety data indicates tolerability of this STIM1/ORAI1 mutations are amenable to pharmacological intervention. If this were so, given that there are no approved treatments or clinical trials ongoing for these rare disorders, it could be envisaged that these agents could also rehabilitate tubular aggregate myopathy patients. In the present contribution we characterized the Ca2+-entry patterns induced by eleven STIM1 and three ORAI1 mutations in heterologous systems or in patient-derived cells, i.e. fibroblasts and myotubes, and evaluated the effect of CIC-37 and CIC-39, two novel store-operated calcium entry modulators. Our data show that all STIM1 and ORAI1 gain-of-function mutations tested, with the possible exception of the R304Q STIM1 mutation, are amenable to inhibition, albeit with slightly different sensitivities, paving the way to the development of SOCE modulators in tubular aggregate myopathies.

Acantholytic Dyskeratosis Post-COVID Vaccination.

ABSTRACT: Acantholytic dyskeratosis mimicking Grover disease as a cutaneous manifestation of a side effect to the Moderna (mRNA-1273) COVID vaccine is rare with only one documented case in the literature to date. Herein, we present a case of an eruptive, erythematous, vesiculopapular rash developing in a patient after the Moderna vaccine. Histopathology of a representative biopsy [x2, done 8 weeks apart] of the rash revealed similar histopathologic findings of patchy suprabasal acantholysis with dyskeratotic keratinocytes and an underlying inflammatory infiltrate of lymphocytes and neutrophils. Direct immunofluorescence was negative. In contrast to the only case previously reported in the literature, a confounding feature in our case, was that patient had a medical history significant for Grover disease, which had been successfully treated with complete resolution and seemed to be in remission. Given the temporal relationship of the onset of the rash to vaccine administration, the changes were likely vaccine-related with the caveat that, in light of the medical history, the differential diagnosis includes reactivation of Grover disease by the vaccine as a trigger factor.

Cutaneous manifestations in an Italian military COVID hub.

BACKGROUND: The outbreak of the pandemic Coronavirus disease 2019 (COVID-19), caused by a novel coronavirus named Severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2), affecting a high number of patients in Italy, forced a great number of doctors, even dermatologists, to work in the first lines in the dedicated departments. We analyzed the features and the incidence of dermatological issues emerged during the hospitalization due to COVID-19 and absent before. METHODS: All the SARS-CoV-2 positive patients hospitalized in Celio Military Hospital - COVID hub no-intensive care wards from March 16, 2020 until May 4, 2020 were evaluated by dermatologists several times during the hospital stay. RESULTS: Ninety-six patients (15 civilians and 81 Italian servicepeople) were enrolled: 34 (35.4%) patients developed cutaneous manifestations; 15 (16.0%) suffered from skin dryness; 5 (5.2%) irritant contact dermatitis; 4 (4.2%) seborrheic dermatitis; 4 (4.2%) morbilliform rashes; 3 (3.1%) petechial rashes and 3 (3.1%) widespread hives. CONCLUSIONS: A deeper knowledge of cutaneous manifestations in military and civilian hospitalized COVID-19 patients could suggest more effective treatments to win the battle against SARS-CoV-2.