title: Genetic characterisation of a cohort of children clinically labelled as GH or IGF1 insensitive: diagnostic value of serum IGF1 and height at presentation.
abstract: OBJECTIVE
  GH insensitivity (GHI) encompasses growth failure, low serum IGF1 and normal/elevated serum GH. By contrast, IGF1 insensitivity results in pre- and postnatal growth failure associated with relatively high IGF1 levels. From 2008 to 2013, 72 patients from 68 families (45M), mean age 7.1 years (0.4-17.0) with short stature (mean height SDS -3.9; range -9.4 to -1.5), were referred for sequencing.
  
  
  METHODS
  As a genetics referral centre, we have sequenced appropriate candidate genes (GHR, including its pseudoexon (6Ψ), STAT5B, IGFALS, IGF1, IGF1R, OBSL1, CUL7 and CCDC8) in subjects referred with suspected GHI (n=69) or IGF1 insensitivity (n=3).
  
  
  RESULTS
  Mean serum IGF1 SDS was -2.7 (range -0.9 to -8.2) in GHI patients and 2.0, 3.7 and 4.4 in patients with suspected IGF1 insensitivity. Out of 69 GHI patients, 16 (23%) (19% families) had mutations in GH-IGF1 axis genes: homozygous GHR (n=13; 6 6Ψ, two novel IVS5ds+1 G to A) and homozygous IGFALS (n=3; one novel c.1291delT). In the GHI groups, two homozygous OBSL1 mutations were also identified (height SDS -4.9 and -5.7) and two patients had hypomethylation in imprinting control region 1 in 11p15 or mUPD7 consistent with Silver-Russell syndrome (SRS) (height SDS -3.7 and -4.3). A novel heterozygous IGF1R (c.112G>A) mutation was identified in one out of three (33%) IGF1-insensitive subjects.
  
  
  CONCLUSIONS
  Genotyping contributed to the diagnosis of children with suspected GHI and IGF1 insensitivity, particularly in the GHI subjects with low serum IGF1 SDS (<-2.0) and height SDS (<-2.5). Diagnoses with similar phenotypes included SRS and 3-M syndrome. In 71% patients, no diagnosis was defined justifying further genetic investigation.
authors.affiliation: Barts and the London School of Medicine and DentistryWilliam Harvey Research Institute, Centre for Endocrinology, Queen Mary University of London, London, UK h.l.storr@qmul.ac.uk.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Storr
authors.affiliation: Barts and the London School of Medicine and DentistryWilliam Harvey Research Institute, Centre for Endocrinology, Queen Mary University of London, London, UK.
authors.forename: Leo
authors.initials: L
authors.lastname: Dunkel
authors.affiliation: Barts and the London School of Medicine and DentistryWilliam Harvey Research Institute, Centre for Endocrinology, Queen Mary University of London, London, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Kowalczyk
authors.affiliation: Barts and the London School of Medicine and DentistryWilliam Harvey Research Institute, Centre for Endocrinology, Queen Mary University of London, London, UK.
authors.forename: Martin O
authors.initials: MO
authors.lastname: Savage
authors.affiliation: Barts and the London School of Medicine and DentistryWilliam Harvey Research Institute, Centre for Endocrinology, Queen Mary University of London, London, UK.
authors.forename: Louise A
authors.initials: LA
authors.lastname: Metherell
mesh_terms: D000293:Adolescent; D015415:Biomarkers / Q000097:blood; D001827:Body Height / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006130:Growth Disorders / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D019382:Human Growth Hormone / Q000097:blood* / Q000235:genetics*; D006801:Humans; D007223:Infant; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism*; D008297:Male
chemical_list: D015415:Biomarkers; C583557:IGF1 protein, human; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I