Thanatophoric dysplasia type II with encephalocele and semilobar holoprosencephaly: Insights into its pathogenesis

Am J Med Genet A. 2011 Jan;155A(1):197-202. doi: 10.1002/ajmg.a.33765.


Thanatophoric dysplasia (TD) is a lethal form of short-limb skeletal dysplasia that is associated with macrocephaly, and variably cloverleaf skull. Two types of TD are clinically recognized, TD1 and TD2, mainly distinguished by their radiographic characteristics. The differences between the two are principally observed in the femur, which appears curved in TD1, while it remains straight but with a proximal medial spike in TD2, and are a less severe overall affectation in TD2. Both types of TD are caused by mutations in different functional domains of the FGFR3 gene. However, whereas several mutations in the different domains of FGFR3 cause TD1, the K650E mutation involving the change of a lysine to glutamic acid ("Lys650Glu") has been found in all TD2 cases to date. Here we describe a newborn infant with TD2 associated with brain defects that have either been infrequently observed (encephalocele) or not hitherto described (holoprosencephaly). Based on recent studies, we consider encephaloceles described in TD to be pseudoencephaloceles, since they are secondary to the intracranial pressure generated by severe hydrocephaly and to severe cranial structural anomalies. Finally, to analyze the mechanisms of holoprosencephaly observed in the case described here, we include a concise review on the current understanding of how FGFs and their receptors are expressed in the rostral signaling center (particularly Fgf8). In addition, we evaluated recent observations that FGF ligands and receptors (including FGFR3) act in concert to organize the whole telencephalon activity, rather than independently patterning different areas.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Encephalocele / genetics*
  • Encephalocele / pathology
  • Fatal Outcome
  • Female
  • Holoprosencephaly / genetics*
  • Holoprosencephaly / pathology
  • Holoprosencephaly / physiopathology*
  • Humans
  • Infant, Newborn
  • Mutation, Missense / genetics
  • Phenotype*
  • Receptor, Fibroblast Growth Factor, Type 3 / genetics*
  • Skull / abnormalities
  • Skull / pathology
  • Thanatophoric Dysplasia / genetics
  • Thanatophoric Dysplasia / pathology


  • FGFR3 protein, human
  • Receptor, Fibroblast Growth Factor, Type 3

Supplementary concepts

  • Thanatophoric dysplasia, type 2