Atypical defects resulting in growth hormone insensitivity.

Besides four well-documented genetic causes of GH insensitivity (GHI) (GHR, STAT5B, IGF1, IGFALS defects), several other congenital and acquired conditions are associated with GHI. With respect to its anabolic actions, GH induces transcription of IGF1, IGFBP3 and IGFALS through a complex regulatory cascade including GH binding to its receptor (GHR), activation of JAK2 and phosphorylation of STAT5b, which then trafficks to the nucleus. GH also activates the MAPK and PI3K pathways. The synthesis of GHR can be reduced by estrogen deficiency or corticosteroid excess, and is possibly decreased in African pygmies. An increased degradation of GHRs because of overexpression of cytokine-inducible SH2-containing protein (CIS) was suggested for some children with idiopathic short stature. Effects on several downstream components of GH signaling were observed for FGF21, cytokines, sepsis, fever and chronic renal failure. In Noonan syndrome and other "rasopathies" the activation of the RAS-RAF-MAPK-ERK pathway leads to inhibition of the JAK/STAT pathway. In contrast, fibroblasts from tall patients with Sotos syndrome showed a downregulation of this axis. Experimental and clinical evidence suggests that the NF-κB pathway plays a role in GH signaling. In a patient with an IκBα mutation presenting with short stature, GHI, severe immune deficiency and other features, NF-κB nuclear transportation and STAT5 and PI3K expression and activity were reduced. A patient with a mosaic de novo duplication of 17q21-25 presented with several congenital anomalies, GHI and mild immunodeficiency. Studies in blood lymphocytes showed disturbed signaling of the CD28 pathway, involving NF-κB and related proteins. Functional studies on skin fibroblasts revealed that NF-κB activation, PI3K activity and STAT5 phosphorylation in response to GH were suppressed, while the sensitivity to GH in terms of MAPK phosphorylation was increased. The expression of one of the duplicated genes, PRKCA, was significantly higher than in control cells, which might be the cause of this clinical syndrome.