title: Splice site mutations in GH1 detected in previously (Genetically) undiagnosed families with congenital isolated growth hormone deficiency type II.
abstract: BACKGROUND
  Congenital isolated growth hormone deficiency (IGHD) is a rare endocrine disorder that presents with severe proportionate growth failure. Dominant (type II) IGHD is usually caused by heterozygous mutations of GH1. The presentation of newly affected family members in 3 families with dominant IGHD in whom previous genetic testing had not demonstrated a GH1 mutation or had not been performed, prompted us to identify the underlying genetic cause.
  
  
  METHODS
  GH1 was sequenced in 3 Caucasian families with a clinical autosomal dominant IGHD.
  
  
  RESULTS
  All affected family members had severe growth hormone (GH) deficiency that became apparent in the first 2 years of life. GH treatment led to a marked increase in height SDS. So far, no other pituitary dysfunctions have become apparent. In the first family a novel splice site mutation in GH1 was identified (c.172-1G>C, IVS2-1G>C). In two other families a previously reported splice site mutation (c.291+1G>A, IVS3+1G>A) was found.
  
  
  CONCLUSIONS
  These data show that several years after negative genetic testing it was now possible to make a genetic diagnosis in these families with a well-defined, clearly heritable, autosomal dominant IGHD. This underscores the importance of clinical and genetic follow-up in a multidisciplinary setting. It also shows that even without a positive family history, genetic testing should be considered if the phenotype is strongly suggestive for a genetic syndrome. Identification of pathogenic mutations, like these GH1 mutations, has important clinical implications for the surveillance and genetic counseling of patients and expands our knowledge on the genotype-phenotype correlation.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: M J E
authors.initials: MJ
authors.lastname: Kempers
authors.forename: S N
authors.initials: SN
authors.lastname: van der Crabben
authors.forename: M
authors.initials: M
authors.lastname: de Vroede
authors.forename: J
authors.initials: J
authors.lastname: Alfen-van der Velden
authors.forename: R T
authors.initials: RT
authors.lastname: Netea-Maier
authors.forename: R A J
authors.initials: RA
authors.lastname: Duim
authors.forename: B J
authors.initials: BJ
authors.lastname: Otten
authors.forename: M
authors.initials: M
authors.lastname: Losekoot
authors.forename: J M
authors.initials: JM
authors.lastname: Wit
mesh_terms: D000328:Adult; D002675:Child, Preschool; D057210:Delayed Diagnosis; D004393:Dwarfism, Pituitary / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D019382:Human Growth Hormone / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010375:Pedigree; D022821:RNA Splice Sites / Q000235:genetics*
chemical_list: D022821:RNA Splice Sites; D019382:Human Growth Hormone