Prepubertal onset of type 2 diabetes in Shashi–Pena syndrome due to ASXL2 mutation

• Published in: American journal of medical genetics. Part A 2022-09, Vol.188 (9), p.2803-2807
• Main Authors: Murphy, Siobhan A., O'Rourke, Niamh E., O'Grady, Michael Joseph
• Format: Article
• Language: English
• Subjects: Animals; Beta cells; Child; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - genetics; Dyslipidemia; Environmental factors; Genetic disorders; Genome-Wide Association Study; Genomes; Glucose tolerance; Homeostasis; Humans; Insulin; Insulin resistance; Insulin Resistance - genetics; Intolerance; Lipodystrophy; Male; Metabolic disorders; Mice; Mutation; Neurodevelopmental disorders; Pediatrics; Peroxisome proliferator-activated receptors; Phenotypes; PPAR gamma - genetics; Puberty; Repressor Proteins - genetics; Shashi–Pena syndrome; Thiazolidinediones; type 2 diabetes
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.62876

Type 2 diabetes remains rare in the pediatric population and the majority of cases occur during puberty. A combination of genetic and environmental factors leads to the development of insulin resistance and β‐cell failure. An increased prevalence is recognized in a number of rare genetic disorders such as Alström and Bardet–Biedl syndromes. Recently, a rare neurodevelopmental disorder, Shashi–Pena syndrome due to the dominant negative effect of heterozygous mutations in additional Sex‐Combs‐Like Genes 2 (ASXL2) has been reported. ASXL2 null mice exhibit glucose intolerance, insulin resistance and lipodystrophy. The regulatory role of ASXL2 in glucose and lipid homeostasis occurs through its interaction with peroxisome proliferator‐activated receptor gamma (PPARγ), a gene implicated in the pathogenesis of type 2 diabetes on genome‐wide association studies. Thiazolidinediones, used for the treatment of type 2 diabetes, exert their effects as direct agonists of PPARγ. We report the first case of type 2 diabetes in Shashi–Pena syndrome, occurring in an 8‐year‐old prepubertal boy with no family history. In addition, the proband had dyslipidemia, and fatty infiltration of the liver with elevated transaminases. Mutation of ASXL2 in humans, through its interaction with PPARγ appears to cause a phenotype of insulin resistance, type 2 diabetes, and dyslipidemia. Further reported cases will assist in confirming this association.