Achondroplasia, the most common form of short-limbed dwarfism in humans, occurs 
between 1 in 15,000 and 40,000 live births. More than 90% of cases are sporadic 
and there is, on average, an increased paternal age at the time of conception of 
affected individuals. More then 97% of persons with achondroplasia have a 
Gly380Arg mutation in the transmembrane domain of the fibroblast growth factor 
receptor (FGFR) 3 gene. Mutations in the FGFR3 gene also result in 
hypochondroplasia, the lethal thanatophoric dysplasias, the recently described 
SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) 
dysplasia, and two craniosynostosis disorders: Muenke coronal craniosynostosis 
and Crouzon syndrome with acanthosis nigricans. Recent evidence suggests that 
the phenotypic differences may be due to specific alleles with varying degrees 
of ligand-independent activation, allowing the receptor to be constitutively 
active. Since the Gly380Arg achondroplasia mutation was recognized, similar 
observations regarding the conserved nature of FGFR mutations and resulting 
phenotype have been made regarding other skeletal phenotypes, including 
hypochondroplasia, thanatophoric dysplasia, and Muenke coronal craniosynostosis. 
These specific genotype-phenotype correlations in the FGFR disorders seem to be 
unprecedented in the study of human disease. The explanation for this high 
degree of mutability at specific bases remains an intriguing question.