Chronic demodicosis in patients with immune dysregulation: An unexpected infectious manifestation of Signal transducer and activator of transcription (STAT)1 gain-of-function

Abstract

Signal transducer and activator of transcription (STAT)1 heterozygous gain-of-function (GOF) mutations are known to induce immune dysregulation and chronic mucocutaneous candidiasis (CMCC). Previous reports suggest an association between demodicosis and STAT1 GOF. However, immune characterization of these patients is lacking. Here, we present a retrospective analysis of patients with immune dysregulation and STAT1 GOF who presented with facial and ocular demodicosis. In-depth immune phenotyping and functional studies were used to characterize the patients. We identified five patients (three males) from two non-consanguineous Jewish families. The mean age at presentation was 11.11 (range = 0.58-24) years. Clinical presentation included CMCC, chronic demodicosis and immune dysregulation in all patients. Whole-exome and Sanger sequencing revealed a novel heterozygous c.1386C>A; p.S462R STAT1 GOF mutation | 57 STAT-1 GOF AND DEMODICOSIS ETHICAL REVIEWThis study was approved by the Institutional Review Board of Hadassah Medical Center (number: HMO-0370-20).

Case Report: A New Gain-of-Function Mutation of STAT1 Identified in a Patient With Chronic Mucocutaneous Candidiasis and Rosacea-Like Demodicosis: An Emerging Association

“…CMC was found in almost all patients (98%); however, the patients displayed a much broader and heterogeneous clinical phenotype, including other skin and invasive infectious diseases, autoimmune diseases (37%), cerebral aneurysm (6%), and/or cancers (6%) (8). Our patient presented CMC, pneumonia, and bronchiectasis, as well as florid rosacea, a clinical form not reported in the two series, but only in 20 other cases among 6 different families (Table 1) (9)(10)(11)(12)(13)(14). The pathophysiology causing rosacea in STAT1 GOF remains unknown.…”

“…Luciferase activity under a GAS promoter was evaluated after 16 h of stimulation with 10 or 1,000 IU/ml of IFN-g or without stimulation. Family members reference: Family 1 (case report), Family 2 (9), Family 3 (10), Family 4 (11), Family 5 (12), Family 6 (13), and Family 7 (14). CMC, chronic mucocutaneous candidiasis; SLE, systematic lupus erythematous; BCG, Bacillus Calmette-Gueŕin vaccine; UTI, urinary tract infection.…”

“…Patients with STAT1 GOF present heterogeneous symptoms; CMC is present in nearly all cases often associated with other infectious (bacterial, fungal, or viral) and noninfectious (autoimmunity/inflammatory, aneurysm, and tumor) clinical features (6,8). Rosacea-like demodicosis is an emerging manifestation reported among the patients with STAT1 GOF, with only a few cases recently described in the literature (9)(10)(11)(12)(13)(14), related to Demodex proliferation. We report the case of a patient with a novel heterozygous STAT1 mutation, shown by functional study to be GOF, who presented CMC associated with recurrent pneumonia and florid rosacea-like demodicosis affecting the center of the face and the eyelids.…”

Human Follicular Mites: Ectoparasites Becoming Symbionts

“…The reason why certain people show pathology in the presence of Demodex has now been unraveled in one case. Chronic demodicosis can be linked to a gain-of-function mutation in the immune response of humans against Demodex ( Martinot et al 2021 ; Shamriz et al 2021 ).…”

Our life companions: the human follicular mite Demodex folliculorum

“…Bit by bit, mechanisms of immune dysregulation are being discovered that lead to pathological levels of Demodex. Paediatric demodicosis, chronic demodicosis, and demodicosis as part of rosacea in humans is caused by a Signal transducer and activator of transcription (STAT) 1 heterozygous gain-of-function (gOF) mutations eventually leading to excessive interferon γ response and compromised T helper cell 17 differentiation (Second et al, 2017;Molho-Pessach et al, 2020;Saez-de-Ocariz et al, 2020;Baghad et al, 2021;Martinot et al, 2021;Shamriz et al, 2021;Zhang et al, 2021).…”