Hypoparathyroidism Retardation and Dysmorphism syndrome due to mutation in Tubulin-specific chaperone E gene as a cause of combined immune deficiency

Abstract Background: Hypoparathyroidism, retardation, and dysmorphism (HRD) syndrome is a disease composed of hypoparathyroidism, growth retardation, developmental delay and typical dysmorphic features, caused by Tubulin-specific chaperone E gene mutation. Many patients succumb in infancy due to overwhelming infections mainly caused by Pneumococcu s spp. Knowledge related to the immune system in these patients is scarce. Purpose: To define the immune phenotype of a cohort of HRD patients including cellular, humoral and neutrophil functions. Methods: The study included HRD patients followed at Soroka University Medical Center. Clinical and immunological data were obtained, including immunoglobulin concentrations, specific antibodies titers, lymphocytes subpopulations, lymphocyte proliferation and neutrophil functions. For detailed methods, please see the Methods section in this article's Online Repository. Results: Nine patients (5 females and 4 males) were enrolled, aged 6 months to 15 years. All received Amoxicillin prophylaxis as part of a routine established previously. Three patients had bacteremia with klebsiella , shigella spp. and Candida. Two patients had confirmed Corona Virus associated Disease 19 (COVID19), both died from this infection. All patients had normal to high IgA level, low anti- Pneumococcal antibodies, and reduced frequency of naive B cell with increased frequency of CD21 low /CD27 - B cell. All patients had abnormal T cell population's distribution, including reduced terminally differentiated effector memory CD8, inverted CD4/CD8 ratio, and poor lymphocytes mitogen induced proliferation. Neutrophil Superoxide production and chemotaxis were normal in all patients tested. Conclusion: HRD is a combined immune deficiency (CID) with severe invasive bacterial and viral infections