Growth hormone (GH) insensitivity due to primary GH receptor deficiency

Abstract

As demonstrated in Table 2, the differential diagnosis of growth hormone insensitivity (GHI) includes a number of discrete disorders that can be broadly classified as primary or secondary forms. We have selected GHRD (Laron syndrome) as the prototypic disorder of GHI, in part because such dramatic and rapid progress has been made in this clinical condition over the last 6 yr. These advances represent the fortunate convergence of: 1) the cloning of the GHR gene and the identification of deletions and mutations of this gene in GHRD; 2) the development of assay methods for measurement of the GHBP, IGF peptides, and binding proteins; 3) the discovery of a larger number of affected individuals than had been previously suspected, including the recognition and description of a large genetically homogeneous population of GHRD patients in Ecuador; and 4) the production of recombinant IGF-I for therapeutic trials in GHRD. Although we are still in the early phases of clinical trials of recombinant hIGF-I in GHRD, preliminary results have been encouraging. Whether this promise translates into genuine improvements in height and body composition, without significant clinical toxicity, remains to be determined. Similarly, the suitability of IGF-I therapy for other, particularly secondary, forms of GHI is still uncertain, although the responsiveness of GHD-IA patients seems to parallel that seen in GHRD (66, 78). The next few years should provide exciting and potentially important new data on the clinical spectrum, biochemical and molecular characteristics, and responsiveness to therapy of syndromes of GHI.

MECHANISMS IN ENDOCRINOLOGY: The multiple facets of GHRH/GH/IGF-I axis: lessons from lifetime, untreated, isolated GH deficiency due to a GHRH receptor gene mutation

“…Among the four known deaths of the Israeli LS cohort, one was due to encephalitis (59). Therefore, both IGHD and GH resistant patients seem vulnerable to infectious diseases in childhood (51,58,59,60).…”

Endocrine Regulation of the Growth Plate

“…GH excess, due to pituitary adenomas in childhood, results in gigantism. Conversely, GH deficiency or insensitivity due to GH-receptor mutations or defects in GH-signaling pathways markedly impairs postnatal growth [10,11,12]. Final height data on patients with untreated isolated GH deficiency suggests that it leads to an average final height SDS of –4.7 (–6.1 to –3.9) [12].…”

The Growth Hormone Cascade: Progress and Long-Term Results of Growth Hormone Treatment in Growth Hormone Deficiency

“…Sequencing the GH-1 gene after PCR amplification in patients with severe IGHD suggests a prevalence of GH-1 mutations of about 10–13%; the most common GH-1 gene alteration is a deletion [67, 68]. Even more rare in the US and Europe are mutations in other members of the GH cascade (GRF, GRF receptor, Pit-1 [POU1F1], PROP1, GH receptor- [GH resistance syndrome] [69], or IGF-I mutations). Both POU1F1 and PROP1 mutations are associated with multiple pituitary deficiencies.…”

“…‘Partial GH resistance’ due to a mutation of one allele of the gene encoding the GH receptor (GHR) has been advanced as a cause of short stature associated with a low serum GHBP level [71, 72]. However, heterozygotes for a mutation in the GHR gene in families with GH resistance [69]are not significantly shorter than ethnically and age-matched normal individuals. In the report [71]suggesting that heterozygous mutations in the gene encoding the GHR were associated with short stature, a polymorphism in the GHR gene was not excluded, nor were the ‘mutations’ studied in in vitro gene expression systems in a search for GHR mutations encoding, for example, an inhibitor of the wild-type receptor protein as described in dominant negative mutation.…”