The d3-Growth Hormone (GH) Receptor Polymorphism Is Associated with Increased Responsiveness to GH in Turner Syndrome and Short Small-for-Gestational-Age Children
G. Binder,
F. Baur,
R. Schweizer and
M. B. Ranke
Section of Pediatric Endocrinology and Growth Research Center, University-Children’s Hospital, 72076 Tübingen, Germany
Address all correspondence and requests for reprints to: PD Dr. Gerhard Binder, Pediatric Endocrinology Section, University-Children’s Hospital, Hoppe-Seyler-Strasse 1, 72076 Tübingen, Germany. E-mail: gerhard.binder{at}med.uni-tuebingen.de.
Context: A protein polymorphism of the GH receptor (GHR) basedon the genomic deletion of exon 3 (d3-GHR) has recently beenlinked to the magnitude of growth response to high-dose recombinanthuman GH (rhGH) therapy of short children without GH deficiency.
Objective: This study tests the novel association in two distinctgroups of rhGH-treated patients, short girls with Turner syndromeand short children born small for gestational age (SGA).
Design: The retrospective study included all children who weretreated with rhGH during the last 18 yr at our hospital.
Patients: Patients with Turner syndrome were defined by thespecific karyotype (n = 53), short children born SGA were determinedby birth length and/or weight less than –2.0 SD scoreand a height at start of rhGH therapy less than –2.0 SDscore (n = 60). Exclusion criteria were puberty, an age lessthan 3.5 or more than 14 yr, and GH deficiency.
Materials and Methods: Growth prediction for the first yearof therapy was calculated on the basis of rhGH dose, age, weight,height, and gender-adjusted midparental height according tothe prediction models by Ranke et al. The GHR-exon 3 locus wasgenotyped using a PCR multiplex assay. GH, IGF-I, and IGF bindingprotein 3 (IGFBP-3) were measured by RIA.
Intervention: For growth promotion, a mean rhGH dose of 38 µg/kg·d(SD, ±8) was administered in Turner syndrome patientsand 56 µg/kg·d (SD, ±11) in short childrenborn SGA.
Results: No significant difference in height, spontaneous heightvelocity, IGF-I, and IGFBP-3 levels was found at the start ofrhGH therapy in the three GHR genotype groups studied. At thefirst year of treatment, girls with Turner syndrome carryingone or two d3-GHR alleles showed a significantly higher incrementin height velocity (P = 0.019) and exceeded their growth predictionsignificantly (P = 0.007), whereas their increments of IGF-Iand IGFBP-3, weight, and height were not significantly different.Carriers of d3-GHR in the group of short children born SGA grewsignificantly faster than predicted (P = 0.023). However, incomparison to the carriers of full-length GHR, gain of heightvelocity was not significantly higher (P = 0.067). The meangain of height associated with d3-GHR accounted for approximately0.75 cm in SGA and 1.5 cm in Turner syndrome during the firstyear of rhGH therapy.
Conclusions: Our data support the theory that there is increasedresponsiveness to high-dose rhGH in association with the d3-GHRgenotype. The magnitude of this effect may depend on the primaryorigin of the short stature.
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