Calcium signaling is fundamental to many cellular processes. An important pathway for increasing intracellular Ca2+ levels is store-operated Ca2+ entry (SOCE) regulated by stromal interaction molecule (STIM1-2), and Ca2+ channels formed by ORAI1-3 proteins. Mutations in the ORAI1 and STIM1 genes that abolish SOCE cause a combined immunodeficiency (CID) syndrome that is accompanied by autoimmunity and nonimmunologic symptoms. We present patients with Anhidrotic Ectodermal Dysplasia with Immunodeficiency (EDA-ID) caused by novel homozygous p.V181SfsX8, p.L194P, and p.G98R mutations in the ORAI1 gene that suppressed ORAI1 protein expression and SOCE in the patients lymphocytes and fibroblasts. A unifying feature of patients with null mutations in ORAI1 is EDA. Anhidrosis was present in patients P1-P4 and confirmed by pilocarpin iontophoresis. Patients had dry and exfoliate skin. They showed signs of heat intolerance and thermoregulatory instability characterized by several attacks of facial flushing accompanied by tachycardia, tachypnea, and hypertension. A skin biopsy showed the presence of eccrine sweat glands in the dermis demonstrating that anhidrosis is not due to a defect in sweat gland development. Recently, we reported that sweat glands require SOCE for opening of the Ca2+-activated chloride channel TMEM16A and thus chloride secretion and sweat production, pointing that anhidrosis in ORAI1-deficient patients could be functional. ORAI1-deficient patients had severe enamel defects diagnosed as hypocalcified amelogenesis imperfecta type III. In contrast, patients with EDA-ID caused by NF-kB signaling defects also have a tooth defect, which is characterized by hypodontia and conical teeth and thus is morphologically easily distinguishable from the enamel defects in ORAI1-deficient patients. ORAI1-deficient patients showed thin and brittle hair. To date, the diagnosis of EDA-ID is limited to patients with defects in NF-kB signaling who are prone to infections with mycobacteria, P.jirovecii, Candida albicans, and, most frequently, pyogenic bacteria caused by hypogammaglobulinemia and failure to mount a specific antibody response to polysaccharide antigens. In contrast, ORAI1-deficient patients are susceptible to an overlapping spectrum of pathogens, but they are also prone to viral infections, including CMV, EBV, RSV, and rotavirus. In addition, AIHA and autoimmune thrombocytopenia are also common in SOCE deficient patients but not NF-kB; instead, patients with NF-kB defects can have inflammatory bowel disease (NF-kB essential modulator colitis). Here we propose that mutations in ORAI1 that abolish SOCE constitute a new form of EDA-ID and are an important differential diagnosis of EDA-ID caused by defects in NF-kB signaling.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology