Growth Hormone Insensitivity, Partial

A number sign (#) is used with this entry because of evidence that partial growth hormone (GH; 139250) insensitivity (GHIP) is caused by heterozygous mutation in the growth hormone receptor gene (GHR; 600946) on chromosome 5p13-p12.

Increased responsiveness to growth hormone is conferred by a polymorphism consisting of deletion of exon 3 of the GHR gene (d3GHR; 600946.0031).

Molecular Genetics

Partial Growth Hormone Insensitivity

In 4 of 14 children with idiopathic short stature, Goddard et al. (1995) identified mutations in the GHR gene (600946.0006-600946.0008). Three children had heterozygous mutations and 1 child had compound heterozygous mutations. The child with compound heterozygous mutations had the poorest response to GH therapy and was more severely affected than his heterozygous parents. Goddard et al. (1995) concluded that some cases of idiopathic short stature can be attributed to partial insensitivity to growth hormone.

Ayling et al. (1997) identified a heterozygous mutation in the GHR gene (600946.0015) in a mother and daughter with idiopathic short stature. Their findings in this family indicated that dominant GHR mutations should be sought in the group of children who had not previously been thought to have an endocrinopathy, namely, those with familial short stature and normal growth hormone-binding protein.

Sanchez et al. (1998) analyzed the GHR gene in 17 subjects with idiopathic short stature and identified a novel heterozygous mutation in 1 subject (height, -1.8 SD). The mutation was also found in his mother and 1 brother, both of whom had significant short stature (height, -2.5 SD and -2.3 SD, respectively). None of the affected members of this family had any features of growth hormone insensitivity syndrome (262500).

Increased Responsiveness to Growth Hormone

The GHR gene contains a polymorphism consisting of a genomic deletion of exon 3 (d3GHR) (600946.0031), which mimics alternative splicing. The polymorphism results in the loss of amino acid residues 7 through 28 and an ala6-to-asp (A6D) substitution in the terminal part of the extracellular receptor domain (Pantel et al., 2000).

Dos Santos et al. (2004) stated that one-half of Europeans are heterozygous or homozygous with respect to the allele encoding the d3GHR isoform, which is dominant over the full-length isoform. They found that the d3GHR isoform was associated with 1.7 to 2 times more growth acceleration induced by GH than the full-length isoform (p less than 0.0001), and that the transduction of GH signaling through d3GHR homo- or heterodimers was approximately 30% higher than through full-length GHR homodimers (p less than 0.0001).

Schreiner et al. (2007) studied association of the GHRd3 isoform with postnatal catch-up growth in very low birth weight preterm infants. Children homozygous or heterozygous for the GHRd3 allele showed a significantly higher rate of postnatal catch-up, compared with those homozygous for GHRfl allele. They concluded that their results define the GHR exon 3 genotype as a predictor for the postnatal growth pattern of very low birth weight preterm infants. Those who carry at least one GHRd3 allele are more likely to catch up.

In a study of 99 adult GH-deficient patients receiving recombinant human GH (rhGH) replacement therapy, Van der Klaauw et al. (2008) found that the d3GHR genotype was associated with differences in efficacy of short-term (1 year), but not long-term (5 years), rhGH replacement with respect to IGF1 and lipid metabolism.

Bougneres (2010) remarked that the exon 3 deletion in GHR seems to influence to a significant degree the response of short children to GH administration and that of acromegalic patients to GHR antagonists, but that the magnitude of the effect remained too small to allow use of this genotype to individualize decisions in clinical endocrinology or to predict therapeutic results. They also noted that the high frequency of the deleted allele (in approximately 25% of Caucasian chromosomes) had not been explained evolutionarily by a credible hypothesis of the potential advantages of harboring the deletion.