SHORT syndrome [MIM# 269880] is an acronym: S = short stature; H = hyperextensibility of joints and/or hernia (inguinal); O=ocular depression; R = Rieger anomaly; T = teething delay. Additional features include characteristic facial features, partial lipodystrophy, insulin resistance, hearing deficits and nephrocalcinosis. Affected individuals have a thin body habitus and developmental milestones and cognition is typically normal. Onset of insulin resistance and/or diabetes mellitus typically occurs in adolescence.
Mutations of the PIK3R1 [OMIM #171833] gene have been identified in patients with SHORT syndrome. PIK3R1 has 16 coding exons and is located at 5q13.1. The phosphatidylinositol 3 kinase pathway regulates fundamental cellular processes and its normal activity is critical for adipose differentiation and insulin signaling. By whole- exome sequencing, mutations in the PIK3R1 gene were identified in 2 unrelated patients with SHORT syndrome by Thauvin-Robinet et al. (2013) and in 1 patient with SHORT syndrome by Dyment et al. (2013). Screening PIK3R1 for mutations in 7 more affected individuals revealed a recurrent missense mutation in all patients.