ORAI1: An Unusual Cause of Combined Immunodeficiency

Introduction Loss-of-function mutations in ORAI1 cause a rare autosomal recessive disorder with an estimated prevalence of <1 in 1,000,000, characterized by multisystemic involvement secondary to impaired intracellular calcium influx. Case Presentation A 3-month-old female born to consanguineous parents, with a family history notable for a sister who died at 2 months of age from respiratory syncytial virus pneumonia and an unexplained fetal loss at 5 months of gestation. She was hospitalized due to respiratory failure. Physical examination revealed moderate protein-caloric malnutrition, anhidrosis, and global hypotonia. Cultures identified Pseudomonas aeruginosa in tracheal secretions; blood cultures grew Candida tropicalis and Klebsiella pneumoniae. Bronchoalveolar lavage revealed a positive PCR for Pneumocystis jirovecii. Immunological evaluation showed normal lymphocyte counts and age-appropriate immunoglobulin levels (IgG, IgA, IgM, and IgE). Lymphoproliferation assay with PHA demonstrated reduced proliferation percentage and division index. Genetic panel revealed a homozygous variant in ORAI1 (c.365T>G, p.Leu122Arg). Treatment included intravenous immunoglobulin every 21 days, antibiotic prophylaxis, and nocturnal noninvasive mechanical ventilation due to severe hypotonia. The patient subsequently underwent hematopoietic stem cell transplantation (HSCT) from a matched sibling donor. Discussion Calcium plays a pivotal role in regulating numerous metabolic processes, signaling pathways, and cellular functions. ORAI1 deficiency severely disrupts calcium influx into cells, leading to multisystemic dysfunction. The condition is characterized by combined immunodeficiency, hypotonia, and ectodermal dysplasia with anhidrosis. HSCT can correct the immunological defect; however, it does not resolve extramedullary manifestations, necessitating long-term multidisciplinary follow-up for affected individuals.