Novel FGF8 mutations associated with recessive holoprosencephaly, craniofacial defects, and hypothalamo-pituitary dysfunction

J Clin Endocrinol Metab. 2011 Oct;96(10):E1709-18. doi: 10.1210/jc.2011-0454. Epub 2011 Aug 10.


Context: Fibroblast growth factor (FGF) 8 is important for GnRH neuronal development with human mutations resulting in Kallmann syndrome. Murine data suggest a role for Fgf8 in hypothalamo-pituitary development; however, its role in the etiology of wider hypothalamo-pituitary dysfunction in humans is unknown.

Objective: The objective of this study was to screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47).

Methods: FGF8 was analyzed by PCR and direct sequencing. Ethnically matched controls were then screened for mutated alleles (n = 480-686). Localization of Fgf8/FGF8 expression was analyzed by in situ hybridization in developing murine and human embryos. Finally, Fgf8 hypomorphic mice (Fgf8(loxPNeo/-)) were analyzed for the presence of forebrain and hypothalamo-pituitary defects.

Results: A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. Second, a heterozygous p.Q216E mutation was identified in a female patient with an absent corpus callosum, hypoplastic optic nerves, and Moebius syndrome. FGF8 was expressed in the ventral diencephalon and anterior commissural plate but not in Rathke's pouch, strongly suggesting early onset hypothalamic and corpus callosal defects in these patients. This was consolidated by significantly reduced vasopressin and oxytocin staining neurons in the hypothalamus of Fgf8 hypomorphic mice compared with controls along with variable hypothalamo-pituitary defects and HPE.

Conclusion: We implicate FGF8 in the etiology of recessive HPE and potentially septo-optic dysplasia/Moebius syndrome for the first time to our knowledge. Furthermore, FGF8 is important for the development of the ventral diencephalon, hypothalamus, and pituitary.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agenesis of Corpus Callosum / complications
  • Agenesis of Corpus Callosum / genetics
  • Arginine Vasopressin / metabolism
  • Craniofacial Abnormalities / genetics*
  • DNA Mutational Analysis
  • Female
  • Fibroblast Growth Factor 8 / genetics*
  • Fibroblast Growth Factor 8 / physiology
  • Holoprosencephaly / genetics*
  • Human Growth Hormone / blood
  • Humans
  • Hydrocortisone / blood
  • Hypothalamic Diseases / genetics*
  • Hypothalamo-Hypophyseal System / physiopathology*
  • Immunohistochemistry
  • In Situ Hybridization
  • Infant
  • Magnetic Resonance Imaging
  • Mutation / physiology*
  • Pituitary Diseases / genetics*
  • Pituitary Gland / growth & development
  • Pituitary Gland / physiology
  • Prosencephalon / growth & development
  • Prosencephalon / physiology
  • Receptor, Fibroblast Growth Factor, Type 1 / biosynthesis
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics
  • Septo-Optic Dysplasia / genetics
  • Thyrotropin / blood


  • FGF8 protein, human
  • Arginine Vasopressin
  • Human Growth Hormone
  • Fibroblast Growth Factor 8
  • Thyrotropin
  • FGFR1 protein, human
  • Receptor, Fibroblast Growth Factor, Type 1
  • Hydrocortisone