Our findings suggest that this patient's IkappaBalpha mutation caused GH and IGF-l resistance which, in turn, contributed to his growth failure. In contrast, none of these effects was elicited by GH or IGF-l in the patient's fibroblasts. In addition, GH stimulated STAT5 phosphorylation and IGF-l mRNA expression in controls ' and the father's fibroblasts, while IGF-l induced PI3K activity and mRNA and protein expression of TDAG51, a target gene for IGF-I. In the fibroblasts of the patient's father (who displays mosaicism for the IkappaBalpha mutation), GH and IGF-l elicited an attenuated stimulatory effect. While both GH and IGF-l induced cell proliferation and NF-kappaB activity in controls' fibroblasts, they had no effect on the patient's fibroblasts. To assess the underlying mechanisms of his GH resistance, we cultured the patient's skin fibroblasts with GH and/or IGF-I. Thus, the diagnosis of GH resistance was made.

Since he was found with low IGF-l and IGFBP-3, and elevated GH secretion, an IGF-l generation test was carried out: baseline IGF-l was low and only responded to a high dose of GH. We have previously reported a child with ectodermal dysplasia, immunodeficiency, and growth retardation, harboring a heterozygous mutation of IkappaBalpha, an essential component of the NF-kappaB pathway. Humans with defects of the NF-kappaB pathway exhibit growth failure, which suggests a possible regulatory role for NF-kappaB in statural growth. We have recently demonstrated that NF-kappaB is expressed in the growth plate and it mediates the growth-promoting effects of IGF-I on chondrogenesis and longitudinal bone growth. NF-kappaB is a family of transcription factors involved in cell proliferation, differentiation, and apoptosis.

Chuck schuldiner zero tolerance rar