PIK3R1 and SHORT syndrome: In contrast to APDS2, constitutional PIK3R1 loss-of-function variants, predominantly in the C-terminal SH2 domain, have been shown to cause SHORT syndrome (short stature–hyperextensibility–hernia–ocular depression–Rieger anomaly–teething delay).26 These variants disrupt association of PI3K holoenzyme with activated RTKs, leading to downstream hypostimulation of the PI3K/AKT axis in response to ligand stimulation.