The d3-growth hormone (GH) receptor polymorphism is associated with increased responsiveness to GH in Turner syndrome and short small-for-gestational-age children.

CONTEXT: A protein polymorphism of the GH receptor (GHR) based on the genomic deletion of exon 3 (d3-GHR) has recently been linked to the magnitude of growth response to high-dose recombinant human GH (rhGH) therapy of short children without GH deficiency.
OBJECTIVE: This study tests the novel association in two distinct groups of rhGH-treated patients, short girls with Turner syndrome and short children born small for gestational age (SGA).
DESIGN: The retrospective study included all children who were treated with rhGH during the last 18 yr at our hospital. PATIENTS: Patients with Turner syndrome were defined by the specific karyotype (n = 53), short children born SGA were determined by birth length and/or weight less than -2.0 sd score and a height at start of rhGH therapy less than -2.0 sd score (n = 60). Exclusion criteria were puberty, an age less than 3.5 or more than 14 yr, and GH deficiency.
MATERIALS AND METHODS: Growth prediction for the first year of therapy was calculated on the basis of rhGH dose, age, weight, height, and gender-adjusted midparental height according to the prediction models by Ranke et al. The GHR-exon 3 locus was genotyped using a PCR multiplex assay. GH, IGF-I, and IGF binding protein 3 (IGFBP-3) were measured by RIA. INTERVENTION: For growth promotion, a mean rhGH dose of 38 mug/kg.d (sd, +/-8) was administered in Turner syndrome patients and 56 mug/kg.d (sd, +/-11) in short children born SGA.
RESULTS: No significant difference in height, spontaneous height velocity, IGF-I, and IGFBP-3 levels was found at the start of rhGH therapy in the three GHR genotype groups studied. At the first year of treatment, girls with Turner syndrome carrying one or two d3-GHR alleles showed a significantly higher increment in height velocity (P = 0.019) and exceeded their growth prediction significantly (P = 0.007), whereas their increments of IGF-I and IGFBP-3, weight, and height were not significantly different. Carriers of d3-GHR in the group of short children born SGA grew significantly faster than predicted (P = 0.023). However, in comparison to the carriers of full-length GHR, gain of height velocity was not significantly higher (P = 0.067). The mean gain of height associated with d3-GHR accounted for approximately 0.75 cm in SGA and 1.5 cm in Turner syndrome during the first year of rhGH therapy.
CONCLUSIONS: Our data support the theory that there is increased responsiveness to high-dose rhGH in association with the d3-GHR genotype. The magnitude of this effect may depend on the primary origin of the short stature.