Splice site mutations in GH1 detected in previously (Genetically) undiagnosed families with congenital isolated growth hormone deficiency type II

Horm Res Paediatr. 2013;80(6):390-6. doi: 10.1159/000355403. Epub 2013 Nov 23.

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.

Conclusion: 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.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Child, Preschool
  • Delayed Diagnosis
  • Dwarfism, Pituitary / diagnosis*
  • Dwarfism, Pituitary / genetics*
  • Female
  • Genetic Testing
  • Human Growth Hormone / genetics*
  • Humans
  • Infant
  • Male
  • Mutation
  • Pedigree
  • RNA Splice Sites / genetics*

Substances

  • RNA Splice Sites
  • Human Growth Hormone

Supplementary concepts

  • Isolated Growth Hormone Deficiency, Type II