title: Expanding the spectrum of mutations in GH1 and GHRHR: genetic screening in a large cohort of patients with congenital isolated growth hormone deficiency.
abstract: BACKGROUND
  It is estimated that 3-30% of cases with isolated GH deficiency (IGHD) have a genetic etiology, with a number of mutations being reported in GH1 and GHRHR. The aim of our study was to genetically characterize a cohort of patients with congenital IGHD and analyze their characteristics.
  
  
  METHODS
  A total of 224 patients (190 pedigrees) with IGHD and a eutopic posterior pituitary were screened for mutations in GH1 and GHRHR. To explore the possibility of an association of GH1 abnormalities with multiple pituitary hormone deficiencies, we have screened 62 patients with either multiple pituitary hormone deficiencies (42 pedigrees), or IGHD with an ectopic posterior pituitary (21 pedigrees).
  
  
  RESULTS
  Mutations in GH1 and GHRHR were identified in 41 patients from 21 pedigrees (11.1%), with a higher prevalence in familial cases (38.6%). These included previously described and novel mutations in GH1 (C182X, G120V, R178H, IVS3+4nt, a>t) and GHRHR (W273S, R94L, R162W). Autosomal dominant, type II IGHD was the commonest form (52.4%), followed by type IB (42.8%) and type IA (4.8%). Patients with type II IGHD had highly variable phenotypes. There was no difference in the endocrinology or magnetic resonance imaging appearance between patients with and without mutations, although those with mutations presented with more significant growth failure (height, -4.7 +/- 1.6 SDS vs. -3.4 +/- 1.7 SDS) (P = 0.001). There was no apparent difference between patients with mutations in GH1 and GHRHR.
  
  
  CONCLUSIONS
  IGHD patients with severe growth failure and a positive family history should be screened for genetic mutations; the evolving endocrinopathy observed in some of these patients suggests the need for long-term follow-up.
authors: Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, University College London Institute of Child Health, London WC1N 1EH, United Kingdom.
authors: Kyriaki S
authors: KS
authors: Alatzoglou
authors: James P
authors: JP
authors: Turton
authors: Daniel
authors: D
authors: Kelberman
authors: Peter E
authors: PE
authors: Clayton
authors: Ameeta
authors: A
authors: Mehta
authors: Charles
authors: C
authors: Buchanan
authors: Simon
authors: S
authors: Aylwin
authors: Elisabeth C
authors: EC
authors: Crowne
authors: Henrik T
authors: HT
authors: Christesen
authors: Niels T
authors: NT
authors: Hertel
authors: Peter J
authors: PJ
authors: Trainer
authors: Martin O
authors: MO
authors: Savage
authors: Jamal
authors: J
authors: Raza
authors: Kausik
authors: K
authors: Banerjee
authors: Sunil K
authors: SK
authors: Sinha
authors: Svetlana
authors: S
authors: Ten
authors: Talat
authors: T
authors: Mushtaq
authors: Raja
authors: R
authors: Brauner
authors: Timothy D
authors: TD
authors: Cheetham
authors: Peter C
authors: PC
authors: Hindmarsh
authors: Primus E
authors: PE
authors: Mullis
authors: Mehul T
authors: MT
authors: Dattani
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005820:Genetic Testing; D018398:Homeodomain Proteins / Q000235:genetics; D019382:Human Growth Hormone / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D007223:Infant; D019901:Locus Control Region; D009154:Mutation; D010375:Pedigree; D018013:Receptors, Neuropeptide / Q000235:genetics*; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000235:genetics*; D055748:SOXB1 Transcription Factors / Q000235:genetics
chemical_list: C489736:HESX1 protein, human; D018398:Homeodomain Proteins; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; C527785:SOX3 protein, human; D055748:SOXB1 Transcription Factors; D019382:Human Growth Hormone; C048250:somatotropin releasing hormone receptor