Clinical issue

Wolf-Hirschhorn syndrome (WHS) is a genetic disorder caused by a partial deletion of the short arm of chromosome 4. WHS patients display a wide variety of phenotypes, but children born with WHS are often diagnosed at birth by characteristic craniofacial features. Other WHS phenotypes include mental retardation, epilepsy, cardiac defects, short stature and skeletal malformations. Haematological disorders and diaphragm defects have also been reported in WHS patients. The genes involved in WHS are not yet known and their identification should help us understand the mechanisms underlying WHS.


In this study, the authors generate a mouse with a loss-of-function mutation in the fibroblast growth factor receptor-like 1 gene (Fgfrl1), which is located on the short arm of chromosome 4 in humans. Fgfrl1 mutant mice recapitulate multiple aspects of WHS, including skeletal malformations and short stature. Additionally, the mouse mutant exhibits abnormal development of permanent laryngeal cartilage elements, providing an explanation for the swallowing problems and impaired speech development observed in humans. Fgfrl1 null mice also show thickening of the cardiac valves and ventricular septation defects similar to common congenital heart malformations in WHS patients. Other phenotypes reminiscent of WHS that are observed in the Fgfrl1 mutant mice include diaphragm defects and haematopoietic disorders.

Implications and future directions

This mouse WHS model with a targeted deletion of Fgfrl1 provides a new tool for studying the genetic mechanisms underlying WHS in humans. Additionally, several forms of cancer and human syndromes that are characterised by craniofacial and skeletal abnormalities are associated with mutations in other FGF receptors. Since FGFRL1 has unique structural characteristics when compared with other FGF receptors, this mouse may provide an insight into the mechanisms of FGF signalling and help explain how FGFRL1 might interact with the other FGF receptors to coordinate the dynamics of different FGF signalling pathways.