In 2003, Kofoed et al. described a girl with severe short stature (height SDS – 7.5 with 16 years old), recurrent infections, and progressive respiratory failure. GH levels after a stimulation test with insulin were very high (53.8 µg/ L), while IGF- 1, IGFBP- 3, and ALS were markedly low, even with r- hGH treatment, and GHBP was normal. The GHR gene was sequenced but it was normal. GHR signalling pathways were then analysed and a homozygous missense mutation was found in STAT5B gene, which prevented STAT5B activation by GH.
Since then, a total of ten patients have been reported harbouring seven different homozygous STAT5B mutations. These patients presented with severe postnatal growth failure (height SDS – 3.0 to – 9.9), normal to elevated GH levels and abnormally low IGF- 1, IGFBP- 3, and ALS, similar to Laron syndrome, but also with manifestations of immune dysregulation, including increased susceptibility for opportunistic infections and autoimmune- associated disorders like lymphocytic interstitial pneumonia and eczema. The immune dysregulation is explained by the fact that other molecules use the STAT5B signalling pathway, including some interleukins. The defect in IL2 action is particularly important, since this interleukin participates in the activation of T lymphocytes and in the development of regulatory T lymphocytes. Other unique features are the elevation of prolactin levels since its negative feedback also depends on STAT5B signalling and the normal levels of GHBP because the defect is intracellular and consequently does not affect the GHR extracellular domain. Heterozygous carriers were approximately 4 cm shorter than non- carrier relatives. They also had lower IGF- 1 and IGFBP- 3 levels and a higher frequency of eczema than their wild- type relatives.
Besides these cases in which genetic inheritance was autosomal recessive, recently patients from three unrelated families with dominant- negative heterozygous STAT5B variants were reported to have postnatal growth failure, eczema, and elevated IgE but no severe immune diseases, expanding the variability of clinical and genetic presentations). Moreover, there are some reports on patients with partial GHI and immune dysfunction who have STAT3 gain of function variants associated with diminished STAT5B transcriptional activity.
