title: Short stature and decreased insulin-like growth factor I (IGF-I)/growth hormone (GH)-ratio in an adult GH-deficient patient pointing to additional partial GH insensitivity due to a R179C mutation of the growth hormone receptor.
abstract: OBJECTIVE
  Genetic factors play an expanding role in understanding growth hormone (GH) disorders, therefore the German KIMS Pharmacogenetics Study was initiated with the aim of genotyping various GH-/IGF-I-axis-related genes of GH-deficient adult patients to investigate genotype:phenotype relationships and response to GH therapy.
  
  
  METHODS
  129 consecutively enrolled GH-deficient adult patients were genotyped for variant 1 (V1) of the alternatively spliced noncoding exons in the 5'-untranslated region and for the nine coding exons of the GH receptor (GHR) gene, which obviously play a striking role in the function of the GH-IGF-I-axis. After detection of a heterozygous, non-synonymous mutation R179C in exon 6 in one single patient with acquired GH-deficiency (GHD) in late adulthood, analysis of her clinical data followed, leading to the diagnosis of mild short stature (-1.5SD). For further endocrine evaluation, five pituitary stimulation tests (arginine) of this patient were statistically compared to stimulation tests (arginine) of ten GH-deficient control patients, retrospectively.
  
  
  RESULTS
  The formerly in patients with Laron syndrome and idiopathic short stature reported mutation R179C leads to an amino acid change from an arginine residue (codon CGC) to a cysteine residue (codon TGC) in position 179 of the extracellular domain of the GHR. Statistical analysis revealed significant decreased IGF-I/GH(0) ratio (p=0.004) and IGF-I/GH(max) ratio (p=0.001) of the index patient compared to the control patients, implying growth hormone resistance of the index patient at the level of the GHR, according to the detected R179C mutation.
  
  
  CONCLUSIONS
  This study reports on the unusual case of a patient with mild short stature, who acquired GHD in late adulthood due to a non-secreting pituitary adenoma and get additionally diagnosed for pre-existing growth hormone insensitivity due to a formerly in two short statured patients described, single, heterozygous, non-synonymous mutation in the GHR. Our findings support the theory that heterozygous mutations in the GHR gene can have mild phenotypical consequences.
authors.affiliation: Division of Endocrinology and Diabetology, University Hospital Giessen and Marburg GmbH, Philipps-University Marburg, Baldingerstrasse, 35033 Marburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Meyer
authors.forename: M
authors.initials: M
authors.lastname: Ipek
authors.forename: A
authors.initials: A
authors.lastname: Keth
authors.forename: T
authors.initials: T
authors.lastname: Minnemann
authors.forename: M A
authors.initials: MA
authors.lastname: von Mach
authors.forename: A
authors.initials: A
authors.lastname: Weise
authors.forename: J R
authors.initials: JR
authors.lastname: Ittner
authors.forename: P P
authors.initials: PP
authors.lastname: Nawroth
authors.forename: U
authors.initials: U
authors.lastname: Plöckinger
authors.forename: G K
authors.initials: GK
authors.lastname: Stalla
authors.forename: U
authors.initials: U
authors.lastname: Tuschy
authors.forename: M M
authors.initials: MM
authors.lastname: Weber
authors.forename: P H
authors.initials: PH
authors.lastname: Kann
mesh_terms: D000328:Adult; D017668:Age of Onset; D019943:Amino Acid Substitution / Q000235:genetics; D001120:Arginine / Q000235:genetics; D001827:Body Height; D003545:Cysteine / Q000235:genetics; D005260:Female; D005838:Genotype; D006130:Growth Disorders / Q000097:blood* / Q000235:genetics*; D019382:Human Growth Hormone / Q000097:blood* / Q000172:deficiency*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis*; D046150:Laron Syndrome / Q000235:genetics; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D011986:Receptors, Somatotropin / Q000235:genetics*
chemical_list: D011986:Receptors, Somatotropin; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D001120:Arginine; D003545:Cysteine