Aristeidis Giannakopoulos, Anastasios D Papanastasiou, Ioannis K Zarkadis, Shayne F Andrew, Ron G Rosenfeld, Alexandra Efthymiadou, Dionisios Chrysis, Vivian Hwa
{"title":"一种影响生长激素受体细胞内结构域的新的杂合从头剪接变体,导致轻度身材矮小。","authors":"Aristeidis Giannakopoulos, Anastasios D Papanastasiou, Ioannis K Zarkadis, Shayne F Andrew, Ron G Rosenfeld, Alexandra Efthymiadou, Dionisios Chrysis, Vivian Hwa","doi":"10.1159/000534183","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>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.</p><p><strong>Case presentation: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":13025,"journal":{"name":"Hormone Research in Paediatrics","volume":null,"pages":null},"PeriodicalIF":2.6000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A Novel, Heterozygous, de novo Splicing Variant Affecting the Intracellular Domain of the Growth Hormone Receptor, and Causing a Mild Short Stature.\",\"authors\":\"Aristeidis Giannakopoulos, Anastasios D Papanastasiou, Ioannis K Zarkadis, Shayne F Andrew, Ron G Rosenfeld, Alexandra Efthymiadou, Dionisios Chrysis, Vivian Hwa\",\"doi\":\"10.1159/000534183\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>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.</p><p><strong>Case presentation: </strong>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. 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A Novel, Heterozygous, de novo Splicing Variant Affecting the Intracellular Domain of the Growth Hormone Receptor, and Causing a Mild Short Stature.
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.
期刊介绍:
The mission of ''Hormone Research in Paediatrics'' is to improve the care of children with endocrine disorders by promoting basic and clinical knowledge. The journal facilitates the dissemination of information through original papers, mini reviews, clinical guidelines and papers on novel insights from clinical practice. Periodic editorials from outstanding paediatric endocrinologists address the main published novelties by critically reviewing the major strengths and weaknesses of the studies.