The neurological manifestations of SHORT syndrome include intrauterine growth restriction, microcephaly, intellectual disability, hearing loss, and speech delay. SHORT syndrome is generally believed to be caused by PIK3R1 gene mutations and impaired PI3K-AKT activation. Recently, a clinical case report described a SHORT syndrome with a novel mutant in PRKCE gene encoding protein kinase Cε (PKCε). However, it remains unclear whether the down-regulation of PKCε gives rise to the symptoms of SHORT syndrome. In this study, we show that a deficiency of PKCε in the central nervous system leads to cerebral and cerebellar atrophy, as well as motor and social deficits. Mechanistically, the deletion of PKCε results in the down-regulation of VEGF/PI3K-induced AKT activation, thereby causing abnormal brain development and dysfunctions. These findings emphasize the roles of PKCε in the development and function of the brain, and offer new perspectives for understanding the neurological manifestations of SHORT syndrome.

Kelch repeat and BTB (POZ) domain-containing 2 (KBTBD2) is known for its pivotal role in metabolic regulation, particularly in adipocytes. However, its significance in skeletal development has remained elusive. Here, we uncover a previously unrecognized function of KBTBD2 in bone formation. Conditional knockout of Kbtbd2 in embryonic osteochondroprogenitor cells or osteoblasts results in impaired osteogenic differentiation, leading to reduced skeletal growth and mineralization. Mechanistically, the loss of KBTBD2 during osteogenesis leads to the accumulation of p85α, a regulatory subunit encoded by phosphoinositide-3-kinase regulatory subunit 1 (Pik3r1), which exerts a potent inhibitory effect on insulin-like growth factor 1 (IGF-1)-induced activation of AKT. Moreover, our study extends the understanding of KBTBD2's relevance beyond bone biology to the context of SHORT syndrome, a rare genetic disorder marked by short stature and various physical abnormalities. We demonstrate that p85α harboring the p.(Arg649Trp) mutation, most frequently found in SHORT syndrome patients, exhibits reduced binding to KBTBD2, leading to impaired IGF-1-mediated activation of AKT. These findings reveal that KBTBD2 is essential in bone formation via regulating the IGF-1 signaling pathway and suggest loss of KBTBD2-mediated regulation of p85α as a potential mechanism for SHORT syndrome.

SHORT syndrome is a rare genetic multisystemic disorder caused by a loss-of-function mutation in the phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) gene. The disease's acronym represents its key features: short stature, hyperextensibility, ocular depression, Rieger anomaly, and teeth delay. Insulin resistance, hyperglycemia, and diabetes mellitus are common endocrinological manifestations of this condition. Currently, there are no established guidelines for the treatment of diabetes in SHORT syndrome patients. In this report, we describe a young adult male patient of Chinese descent with atypical diabetes mellitus associated with SHORT syndrome. This case was challenging due to the patient's young-onset diabetes and poor diabetes control, complicated by insulin resistance from lipodystrophy, and a strong aversion to insulin injections. By utilizing a combination of oral anti-glycemic agents with complementary mechanisms of action (metformin, sodium-glucose co-transporter 2 (SGLT-2) inhibitors, sulfonylureas, thiazolidinediones, and GLP-1 agonists), insulin therapy was delayed. The patient's blood glucose levels improved significantly, with HbA1c decreased from 14% to 8.8% within 6 months of starting the multi-agent regimen, and further improved to 7.4% with a fasting plasma glucose of 4.8 mmol/L. With an oral medication regimen that the patient found acceptable, both his quality of life and adherence to treatment improved. These findings provide useful insights into tailoring an individualized diabetes treatment plan.

Insulin sensitivity decreases during pregnancy; hence, higher insulin requirements occur in cases of preexisting insulin resistance. In pregnant patients with extremely high insulin requirements, a monogenic etiology may be present. We present 2 cases of severe insulin resistance in pregnancy. Heterozygous insulinreceptor (INSR) pathogenic gene variants were detected in a 31-year-old woman with a high body mass index and type 2 diabetes mellitus who needed up to 2200 units/day of insulin. A 25-year-old woman with lipodystrophy and insulin resistance, associated with SHORT syndrome (short stature, hyperextensible elbows, ocular depression, teeth eruption) due to a heterozygous PIK3R1 pathogenic variant developed insulin requirements up to 766 units/day after exposure to exogenous steroids. Few case reports describe patients with INSR variants in pregnancy but none among women with coexisting obesity. No previous cases of SHORT syndrome in pregnancy have been described. These cases serve as a reminder to consider differential diagnoses for severe insulin resistance presenting in pregnancy and highlight a need for future research regarding treatment options.

We report a case of metreleptin use in a patient with SHORT syndrome, a rare congenital disorder characterized by partial lipodystrophy, distinctive dysmorphic features, and severe insulin resistance. The patient was initially misdiagnosed with type 1 diabetes in early childhood because of insulin dependence, but genetic testing later confirmed a pathogenic PIK3R1 variant consistent with SHORT syndrome. Despite high-dose insulin therapy and adjunctive agents, glycemic control remained poor. Introduction of metreleptin led to a rapid and sustained improvement in glycemic control, with a marked reduction in insulin requirements. Notably, the patient did not exhibit hepatic steatosis or hypertriglyceridemia-features typically associated with metreleptin-responsive lipodystrophy-suggesting a broader therapeutic potential of the drug. Treatment interruption due to weight issues resulted in swift metabolic deterioration, including a sharp rise in glycosylated hemoglobin and increased insulin needs. Upon reinitiation, metabolic parameters rapidly improved. This case highlights the potential utility of metreleptin in treating severe insulin resistance in SHORT syndrome, even in the absence of classical metabolic complications. Further studies are needed to define its role in atypical lipodystrophy syndromes with unusual metabolic phenotypes.