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Exon 3-Deleted/Full-Length Growth Hormone Receptor Polymorphism Genotype Frequencies in Spanish Short Small-for-Gestational-Age (SGA) Children and Adolescents (n = 247) and in an Adult Control Population (n = 289) Show Increased fl/fl in Short SGA

Department of Pediatrics (L.A., C.E., A.C., A.P.-A., R.A., M.C.), Hospital Vall d’Hebron, Autonomous University, 08035 Barcelona, Spain; Medical Unit (R.E.), Pfizer Spain, 28108 Madrid, Spain; WW Medical Endocrine Care (H.W.), Pfizer GmbH, 76032 Karlsruhe, Germany; WW Endocrine Care Team (L.F.), Pfizer Health AB, 191–90 Sollentuna, Sweden; and Clinical Polyomics (L.A.P.), Pfizer Inc, New York, New York 10017

Address all correspondence and requests for reprints to: Laura Audí, Unidad Investigación Endocrinología Pediátrica, Hospital Vall d’Hebron, Paseo Vall d’Hebron 119, 08035 Barcelona, Spain. E-mail: laudi{at}ir.vhebron.net.

Context: A polymorphism in the human GH receptor gene (d3/fl-GHR) resulting in genomic deletion of exon 3 has been associated with the degree of height increase in response to GH therapy.

Objective: The objective of the study was to evaluate the frequencies of d3/fl-GHR polymorphism genotypes in control and short small-for-gestational-age (SGA) populations.

Design: An adult control population with heights normally distributed (ACPNH) between –2 and +2 SD score (SDS) and a short non-GH-deficient SGA child population were selected.

Setting: Thirty Spanish hospitals participated in the selection of the short non-GH-deficient SGA children in the setting of a controlled, randomized trial, and one of these hospitals selected the ACPNH.

Controls and Patients: Two hundred eighty-nine adult subjects of both sexes constituted the ACPNH and 247 children and adolescents of both sexes the short SGA patients.

Main Outcome Measures: Heights and weights were recorded in the ACPNH, and auxologic and biochemical data were recorded at each hospital for the SGA patients; d3/fl-GHR genotypes were determined and data analyzed in a single hospital.

Results: In short SGA patients, d3/fl-GHR genotype frequencies were significantly different from those in ACPNH, with a higher frequency of fl/fl genotype (P < 0.0001). In ACPNH, a trend toward diminished d3/d3 genotype frequency was observed in the shortest height group (height –1 SDS and –2 SDS, n = 60).

Conclusions: Our data showed significant differences in the frequency distribution of the d3/fl-GHR genotypes between a normally distributed adult height population and short SGA children, with the biologically less active fl/fl genotype being almost twice as frequent in SGA patients. These data suggest that the d3/fl-GHR polymorphism might be considered among the factors that contribute to the phenotypic expression of growth.

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