title: Genetic analysis of GHR should contain sequencing of all coding exons and specific intron sequences, and screening for exon deletions.
abstract: BACKGROUND
  The work-up of patients with clinical and/or biochemical features of growth hormone insensitivity (GHI) usually contains genetic analysis of the growth hormone receptor (GHR) gene, and if negative, of STAT5B, IGFALS and IGF1. In a previous report we described 2 siblings presenting with short stature, low IGF-1 levels, elevated GH secretion and no increase of IGF-1 after 1 week of GH administration. Repeated analysis of the GHR showed no abnormalities; however, further testing revealed a heterozygous STAT5B defect in both siblings.
  
  
  METHODS
  Two boys of Surinam-Hindustan origin showed growth failure up to the age of 6-7 years, followed by partial catch-up growth associated with increasing body mass index. Reanalysis of GHR including published intronic sequences was performed on the patients' DNA collected 7 years earlier.
  
  
  RESULTS
  The heterozygous STAT5B variant proved to be functionally benign. A homozygous intronic mutation of the GHR, c.618+792A>G (IVS6+792A>G), was subsequently found, resulting in the activation of pseudoexon 6ψ, and explaining the GHI phenotype of the patients.
  
  
  CONCLUSIONS
  An intronic GHR mutation should be considered in all patients with signs of GHI and no coding exon mutations, even if the phenotype is mild and even if other genetic variants have been found.
authors: Department of Pediatrics, VU University Medical Center, Amsterdam, The Netherlands.
authors: M J E
authors: MJ
authors: Walenkamp
authors: J
authors: J
authors: Klammt
authors: E
authors: E
authors: Feigerlova
authors: M
authors: M
authors: Losekoot
authors: H A
authors: HA
authors: van Duyvenvoorde
authors: V
authors: V
authors: Hwa
authors: R
authors: R
authors: Pfäffle
authors: J M
authors: JM
authors: Wit
mesh_terms: D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods*; D005091:Exons / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods; D006130:Growth Disorders / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics*; D008297:Male; D010375:Pedigree; D011986:Receptors, Somatotropin / Q000235:genetics*; D017384:Sequence Deletion; D035781:Siblings
chemical_list: D011986:Receptors, Somatotropin