Novel Variant in the USP9X Gene Is Associated with Congenital Heart Disease in a Male Patient: A Case Report and Literature Review.

Introduction: The X-chromosomal USP9X gene encodes a deubiquitylating enzyme involved in protein turnover and TGF-ß signaling during fetal and neuronal development. USP9X 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, USP9X missense variants in males often result in partial rather than complete LOF, specifically affecting neuronal migration and development. USP9X 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. Case Presentation: 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 USP9X gene (c.5470A>G, p.Met1824Val) that was never reported in the literature. Conclusion: We provide an overview of the available literature on USP9X 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 USP9X variants in neuronal development and corroborate the possible association between the novel USP9X variant and congenital heart malformation.

Safety, metabolic and psychological outcomes of Medtronic MiniMed 670G in children, adolescents and young adults: a systematic review.

Hybrid closed loop (HCL) systems are the combination of a pump for insulin delivery and a glucose sensor for continuous glucose monitoring. These systems are managed by an algorithm, which delivers insulin on the basis of the interstitial glucose levels. The MiniMed™ 670G system was the first HCL system available for clinical purpose. In this paper, we reviewed the literature about metabolic and psychological outcomes in children, adolescents and young adults with type 1 diabetes treated with MiniMed™ 670G. Only 30 papers responded to the inclusion criteria and thus were considered. All the papers show that the system is safe and effective in managing glucose control. Metabolic outcomes are available up to 12 months of follow-up; longer study period are lacking. This HCL system may improve HbA1c up to 7.1% and time in range up to 73%. The time spent in hypoglycaemia is almost neglectable. Better improvement in blood glucose control is observed in patients with higher HbA1c at HCL system start and larger daily use of auto-mode functionality.     Conclusion: The Medtronic MiniMed™ 670G is safe and well accepted, without any increase in the burden for patients. Some papers report an improvement in the psychological outcomes, but other papers do not confirm this finding. So far, it significantly improves the management of diabetes mellitus in children, adolescents and young adults. Proper training and support by the diabetes team are mandatory. Studies for a period longer than 1 year would be appreciated to better understand the potentiality of this system. What is Known: • The Medtronic MiniMedTM 670G is a hybrid closed loop system which combines a continuous glucose monitoring sensor with an insulin pump. • It has been the first hybrid closed loop system available for clinical purpose. Adequate training and patients support play a key role in diabetes management. What is New: • The Medtronic MiniMedTM 670G may improve HbA1c and CGM metrics up to 1-year of follow-up, but the improvement appears lower than advanced hybrid closed loop systems. This system is effective to prevent hypoglycaemia. • The psychosocial effects remain less understood in terms of improvement of psychosocial outcomes. The system has been considered to provide flexibility and independence by the patients and their caregivers. The workload required to use this system is perceived as a burden by the patients who decrease the use of auto-mode functionality over time.

Early-Onset Diabetes in an Infant with a Novel Frameshift Mutation in LRBA.

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.