Kofoed and colleagues described a patient with a homozygous mutation in the gene for STAT5b, resulting in growth hormone insensitivity. The girl had abnormal postnatal growth, facial dysmorphism, elevated GH levels after insulin-arginine stimulation, and markedly reduced serum concentrations of IGF-1, IGFBP-3 and acid labile-subunit. Serum concentrations of these proteins remained abnormally low despite 7 days of treatment with GH, and the growth rate failed to increase in response to one year of treatment. Concentrations of GHBPs were normal, reflecting the fact that her GHR gene and protein were normal. This patient had no family history of growth retardation, though the parents were first cousins.

Kofoed EM, Hwa V, Little B, et al. Growth Hormone Insensitivity Associated with STAT5b Mutation. N Engl J Med 2003;349:1139-1147.

Editor’s Comment: The authors described a novel mechanism for impaired growth in a patient with severe short stature. This was clearly demonstrated by sophisticated analysis. The finding of elevated serum GH levels after stimulatory tests, in conjunction with low levels of IGF-1 and IGFBP-3, established the presence of GH resistance. Unlike patients with the classic Laron syndrome, this patient had normal levels of GHBP, indicating that the defect was distal to the extra cellular GH receptor domain. A homozygous missense mutation in the STAT5b gene resulted in loss of GH action due to a post-receptor abnormality in the GH-signaling cascade. The GH-activated intracellular signaling involves several steps and, theoretically, each one of these steps could fail and produce GH insensitivity. The role of STATs in stature was reviewed in an accompanying editorial. 1 Eugster and Pescovitz depicted the GH-activated intracellular signaling cascade which is reproduced here. (Figure).

Fima Lifshitz, MD

References - (linked to )

1. Eugster EA, Pescovitz OH. N Engl J Med 2003;349:1110-1112.