The term of GH insensitivity syndrome (GHIS) describes a group of inherited disorders characterized by a reduction in the biological effects of GH in the presence of normal or elevated serum GH concentrations.
The first report of GHIS of genetic origin was published by Laron et al in 1966 (17). Since then the description of this disorder has expanded, as has the spectrum of clinical and biochemical abnormalities. The clinical disorder known as Laron syndrome has been shown to be associated with defects of the GHR gene (71). Due to the large number of established GHR mutations it is impossible to describe them all in this chapter but this topic has been recently reviewed in great detail (72).
The clinical characteristics of the affected patients are very similar to those seen in GH deficiency secondary to mutations in the GH gene, namely hypoglycemic episodes, severe growth failure and a typical craniofacial appearance (Figure 2). In terms of linear growth, the most striking feature is the rapid decrease in height SDS during the early post-natal years. In the first three years of life there is a loss of approximately 3 SDS per year as demonstrated in the Ecuadorian patients, the largest kindred with this disorder (73). Intellectual retardation has been described in the original Israeli populations but is not a universal finding.
The heterogeneity of clinical and biochemical features has been demonstrated in a series of patients studied in Europe (74). A recent analysis has been performed of 59 of the patients in this European series who were classified into "classical" or atypical based on their facial appearance. Fifty patients had classical facial features whereas seven patients classified as "atypical" had normal facies (75). In addition, patients with atypical GHIS had less height deficit (height SDS -4.0 +/- 1.4) compared with patients with classical GHIS (-8.6+/-2.4).
Severe short stature with or without classical features of Laron syndrome with normal to high serum GH concentrations, very low serum IGF-I, IGFBP-3 and ALS levels suggest impaired GH effects as described earlier. GH binding protein (GHBP), the circulating form of the extracellular domain of the GHR, was initially found to be absent but recent reports have found that some patients with GHIS may have normal or even elevated serum GHBP (74). Usually more atypical patients had normal GHBP.
The molecular defect in GHIS originates in the GHR gene, with over 30 mutations now reported. The majority of the molecular defects of the GHR have been point mutations in exons 2-7 of the GHR gene, which encodes the extracellular domain of the receptor and therefore these mutations impaired GH binding (74).
A recent report of a 16-year old Argentinean girl from consanguineous parents, presenting with a clinical history of severe postnatal growth failure (Ht SDS -7.5), frequent upper respiratory infections, with immune dysfunction and marked IGF-I, IGFBP-3 and ALS deficiencies. She failed to respond to GH treatment and genetic studies were performed to elucidate the molecular defect associated with the clinical and biochemical diagnosis of GHI. Molecular studies showed that she has a normal GH receptor gene but a novel GH post-receptor defect was identified. A homozygous missense mutation of the STAT5 gene was identified and the resulting protein proven to be incapable of phosphorylation in response to either GH or gamma interferon (75). We have identified two siblings with clinical and biochemical features of GHI owing to a molecular defect in STAT5b (our unpublished data), and the frequency of abnormalities in STAT5b as a cause of GHI remains unknown.