A Novel, Heterozygous, de novo Splicing Variant Affecting the Intracellular Domain of the Growth Hormone Receptor, and Causing a Mild Short Stature.

Autor:	Giannakopoulos A; Division of Endocrinology, Department of Pediatrics, Medical School, University of Patras, Patras, Greece., Papanastasiou AD; Department of Biology Medical School, University of Patras, Patras, Greece., Zarkadis IK; Department of Biology Medical School, University of Patras, Patras, Greece., Andrew SF; Division of Endocrinology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati School of Medicine, Cincinnati, Ohio, USA., Rosenfeld RG; Division of Endocrinology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati School of Medicine, Cincinnati, Ohio, USA., Efthymiadou A; Division of Endocrinology, Department of Pediatrics, Medical School, University of Patras, Patras, Greece., Chrysis D; Division of Endocrinology, Department of Pediatrics, Medical School, University of Patras, Patras, Greece., Hwa V; Division of Endocrinology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati School of Medicine, Cincinnati, Ohio, USA.
Jazyk:	angličtina
Zdroj:	Hormone research in paediatrics [Horm Res Paediatr] 2024; Vol. 97 (4), pp. 397-403. Date of Electronic Publication: 2023 Sep 19.
DOI:	10.1159/000534183
Abstrakt:	Introduction: Although the majority of growth hormone insensitivity syndrome (GHIS) cases are classical, the spectrum of clinical phenotypes has expanded to include "atypical" GHIS subjects with milder phenotypes due to very rare heterozygous growth hormone receptor (GHR) mutations with dominant negative effects. Case Presentation: A 13-year-old pubertal boy presented with short stature (-1.7 SDS) and delayed bone age (11.5 years). His serum IGF-1 was low (16 ng/mL; reference range: 179-540). IGFBP-3 (1.3 mg/L; 3.1-9.5) and ALS (565 mU/mL; 1,500-3,500) were also low. GH stimulation test was normal, and GHBP was markedly elevated (6,300 pmol/L; 240-3,000). Additionally, the boy had insulin resistance and liver steatosis. His final height reached -1.8 SDS, which was 3.0 SDS below his mid-parental height. GHR gene from genomic DNA and established primary fibroblast culture was analyzed and a synonymous heterozygous GHR: c.945G>A variant, in the last nucleotide of exon 9 (encoding intracellular domain of GHR) was identified. In vitro analysis of the GHR cDNA demonstrated a splicing defect, leading to the heterozygous excision of exon 9. The final predicted product was a truncated GHR protein which explained the elevated GHBP levels. Conclusion: We describe the first synonymous heterozygous GHR splicing variant in the exon 9-encoding part of the intracellular domain of GHR identified in a patient with mild short stature, thus supporting the continuum of genotype-phenotype of GHIS. (© 2023 S. Karger AG, Basel.)
Databáze:	MEDLINE
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