Search

Wolfram syndrome patients are mainly characterised by juvenile onset diabetes mellitus and optic atrophy. A synonym is the acronym DIDMOAD: diabetes insipidus, diabetes mellitus, optic atrophy, deafness. Diabetes insipidus and sensorineural high-frequency hearing impairment are important additional features. This rare autosomal recessively inherited neurodegenerative syndrome is caused by mainly inactivating mutations in the WFS1 gene. It is located at chromosome 4p16 and encodes wolframin, a transmembrane protein. No function has yet been ascribed to this protein.

One of the genes involved in craniosynostosis syndromes is the fibroblast growth factor receptor 2 (FGFR2) gene, a tyrosine kinase receptor gene. Upon ligand binding the FGFR2 receptors dimerise, and this is followed by activation of the intracellular tyrosine kinase domains. This initiates a cascade of signals that influence cell division and differentiation. FGFR2 mutations have been found in the Apert, Crouzon and Pfeiffer craniosynostosis syndromes. Most mutations are gain of function mutations, inducing ligand-independent receptor activation or altered ligand binding. With the exception of Apert syndrome, there is no clear genotype-phenotype correlation. Many different mutations have been found in Pfeiffer and Crouzon syndrome, but all of the mutations occur in the same extracellular region of the receptor. Identical mutations have been found in Pfeiffer and Crouzon syndrome. So within one family, both Crouzon and Pfeiffer syndrome may occur. Mutations in other FGFR-genes have also been found in craniosynostosis syndromes.