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We describe early-onset diabetes in a 6-month-old patient carrying an LRBA gene mutation. Mutations in this gene cause primary immunodeficiency with autoimmune disorders in infancy. At admission, he was in diabetic ketoacidosis, and treatment with fluid infusion rehydration and then i.v. insulin was required. He was discharged with a hybrid closed-loop system for insulin infusion and prevention of hypoglycemia (Minimed Medtronic 670G). He underwent a next-generation sequencing analysis for monogenic diabetes genes, which showed that he was compound heterozygous for two mutations in the LRBA gene. In the following months, he developed arthritis of hands and feet, chronic diarrhea, and growth failure. He underwent bone marrow transplantation with remission of diarrhea and arthritis, but not of diabetes and growth failure. The blood glucose control has always been at target (last HbA1c 6%) without any severe hypoglycemia. LRBA gene mutations are a very rare cause of autoimmune diabetes. This report describes the clinical course in a very young patient. The hybrid closed-loop system was safe and efficient in the management of blood glucose. This report describes the clinical course of diabetes in a patient with a novel LRBA gene mutation.

<b><i>Introduction:</i></b> The X-chromosomal <i>USP9X</i> gene encodes a deubiquitylating enzyme involved in protein turnover and TGF-β signaling during fetal and neuronal development. <i>USP9X</i> variants in females are primarily associated with complete loss-of-function (LOF) alleles, leading to neurodevelopmental delay and intellectual disability, as well as a wide range of congenital anomalies. In contrast, <i>USP9X</i> missense variants in males often result in partial rather than complete LOF, specifically affecting neuronal migration and development. <i>USP9X</i> variants in males are associated with intellectual disability, behavioral disorders, global developmental delay, speech delay, and structural CNS defects. Facial dysmorphisms are found in almost all patients. <b><i>Case Presentation:</i></b> We report the case of an Italian boy presenting dysmorphism, intellectual disability, structural brain anomalies, and congenital heart disease. Using next-generation sequencing analysis, we identified a hemizygous de novo variant in the <i>USP9X</i> gene (c.5470A&#x3e;G, p.Met1824Val) that was never reported in the literature. <b><i>Conclusion:</i></b> We provide an overview of the available literature on <i>USP9X</i> variants in males, in order to further expand the genotypic and phenotypic landscape of male-restricted X-linked mental retardation syndrome. Our findings confirm the involvement of <i>USP9X</i> variants in neuronal development and corroborate the possible association between the novel <i>USP9X</i> variant and congenital heart malformation.

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