Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia

J Clin Endocrinol Metab. 2012 Apr;97(4):E694-9. doi: 10.1210/jc.2011-2938. Epub 2012 Feb 8.


Context: Kallmann syndrome (KS), combined pituitary hormone deficiency (CPHD), and septo-optic dysplasia (SOD) all result from development defects of the anterior midline in the human forebrain.

Objective: The objective of the study was to investigate whether KS, CPHD, and SOD have shared genetic origins.

Design and participants: A total of 103 patients with either CPHD (n = 35) or SOD (n = 68) were investigated for mutations in genes implicated in the etiology of KS (FGFR1, FGF8, PROKR2, PROK2, and KAL1). Consequences of identified FGFR1, FGF8, and PROKR2 mutations were investigated in vitro.

Results: Three patients with SOD had heterozygous mutations in FGFR1; these were either shown to alter receptor signaling (p.S450F, p.P483S) or predicted to affect splicing (c.336C>T, p.T112T). One patient had a synonymous change in FGF8 (c.216G>A, p.T72T) that was shown to affect splicing and ligand signaling activity. Four patients with CPHD/SOD were found to harbor heterozygous rare loss-of-function variants in PROKR2 (p.R85G, p.R85H, p.R268C).

Conclusions: Mutations in FGFR1/FGF8/PROKR2 contributed to 7.8% of our patients with CPHD/SOD. These data suggest a significant genetic overlap between conditions affecting the development of anterior midline in the human forebrain.

Trial registration: NCT00494169.

Publication types

  • Comparative Study
  • Controlled Clinical Trial
  • Multicenter Study

MeSH terms

  • Animals
  • Female
  • Fibroblast Growth Factor 8 / genetics*
  • Fibroblast Growth Factor 8 / metabolism
  • Genetic Association Studies
  • Heterozygote
  • Humans
  • Hypopituitarism / genetics*
  • Hypopituitarism / metabolism
  • Kallmann Syndrome / genetics*
  • Kallmann Syndrome / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Mutation*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism
  • Neurons / pathology
  • Pituitary Gland, Posterior / metabolism
  • Pituitary Gland, Posterior / pathology
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics*
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Peptide / genetics*
  • Receptors, Peptide / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Septo-Optic Dysplasia / genetics*
  • Septo-Optic Dysplasia / metabolism
  • Signal Transduction
  • United Kingdom
  • United States


  • FGF8 protein, human
  • Nerve Tissue Proteins
  • PROKR2 protein, human
  • Receptors, G-Protein-Coupled
  • Receptors, Peptide
  • Recombinant Fusion Proteins
  • Fibroblast Growth Factor 8
  • FGFR1 protein, human
  • Receptor, Fibroblast Growth Factor, Type 1

Associated data