title: Genetic screening of a Dutch population with isolated GH deficiency (IGHD).
abstract: OBJECTIVE
  Five per cent to 30% of cases of idiopathic isolated GH deficiency (IGHD) have first-degree relatives with short stature, which is suggestive of a genetic aetiology. The HYPOPIT study aimed to obtain an overall picture of gene encoding pituitary GH (GH1) and gene encoding GH releasing hormone-receptor (GHRHR) defects in a Dutch IGHD cohort and to relate them with clinical parameters.
  
  
  METHODS
  Genetic analysis was performed of exons and exon-intron boundaries of GH1 and GHRHR in 89 Caucasian IGHD patients from 81 families, using denaturing high-performance liquid chromatography (dHPLC), DNA sequencing and multiplex ligation-dependent probe amplification. In addition, we performed functional studies on novel identified GH1 exonic variants.
  
  
  RESULTS
  Five different heterozygous GH1 mutations were present in 5 out of 81 participating families (6.1%), whereas no mutations in GHRHR were found. Patients with IGF-I SDS < -4.0 and peak GH levels < 5.7 mU/l had a mutation frequency of 40%, in contrast to 6.8% in patients with only one criterion, and 0.0% in patients with none of these criteria (P = 0.00007). Five new GH1 and two GHRHR variants were also identified; two of them (GH1 F92L and D153H) caused a marked reduction of GH secretion in vitro.
  
  
  CONCLUSIONS
  GH1 and GHRHR mutations are rare in Caucasian Dutch IGHD patients, which suggests the involvement of other genetic determinants in the aetiology of IGHD. IGF-I < -4.0 and peak GH levels < 5.7 mU/l are strong predictors of GH1 mutations in the studied population.
authors.affiliation: Department of Pediatrics, Division of Pediatric Endocrinology, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands. l.degraaff@erasmusmc.nl
authors.forename: Laura C G
authors.initials: LC
authors.lastname: de Graaff
authors.forename: Jesús
authors.initials: J
authors.lastname: Argente
authors.forename: Danielle C M
authors.initials: DC
authors.lastname: Veenma
authors.forename: Maaike A C
authors.initials: MA
authors.lastname: Herrebout
authors.forename: Edith C H
authors.initials: EC
authors.lastname: Friesema
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Madeleine L
authors.initials: ML
authors.lastname: Drent
authors.forename: Angel
authors.initials: A
authors.lastname: Campos-Barros
authors.forename: Anita C S
authors.initials: AC
authors.lastname: Hokken-Koelega
mesh_terms: D000818:Animals; D001827:Body Height; D019556:COS Cells; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D005820:Genetic Testing; D014644:Genetic Variation; D006579:Heterozygote; D019382:Human Growth Hormone / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D009426:Netherlands; D010641:Phenotype; D018013:Receptors, Neuropeptide / Q000235:genetics; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D044465:White People / Q000235:genetics
chemical_list: D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D011994:Recombinant Proteins; D019382:Human Growth Hormone; C048250:somatotropin releasing hormone receptor