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

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 ß-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.

Adolescent onset of autoimmune polyglandular syndrome type 2.

An adolescent female was evaluated for fatigue, anorexia and unintentional weight loss of 7 kg. Initial investigations revealed subclinical autoimmune thyroid dysfunction, which progressed to overt hypothyroidism necessitating thyroxine replacement. She had entered early puberty, but this did not appear to be progressing. A high index of suspicion for coexisting endocrinopathies resulted in a diagnosis of Addison's disease and consequently autoimmune polyglandular syndrome type 2 (Schmidt syndrome). While basal gonadotropins were normal, anti-Mullerian hormone was low and ovarian autoantibodies were positive, consistent with preclinical premature ovarian failure. Glucocorticoid and mineralocorticoid replacement were instituted. Puberty progressed and menarche was subsequently attained. Screening for other autoantibodies was undertaken; however, none are positive to date.