Table 1.

Skeletal dysplasias associated with FGFR3 mutations.

Disorder	Mutationa	Mechanism	Key features	Inheritanceb
Achondroplasia136, 140, 141	G380R (transmembrane domain)	Gain-of-function mutation results in decreased inhibition of endochondral ossification	Short stature, rhizomelic limb shortening, short fingers and toes, large head with prominent forehead, small midface with flattened nasal bridge, spinal kyphosis/lordosis, varus/valgus deformities	Autosomal dominant; sporadic
Hypochondroplasia139, 140, 142, 152	N540K (first tyrosine kinase domain); missense mutations (extra-cellular domain)	Gain-of-function mutations result in premature fusion of growth plates in vertebral column and long bones	Short stature, short limbs, increased head circumference, normal facies	Autosomal dominant; sporadic
Thanatophoric dysplasia140, 141, 143, 153, 154, 155	R248C (extra-cellular domain; type I) K650E (second tyrosine kinase domain; type II)	Gain-of-function mutations result in ligand-independent receptor activation	Early death, extremely short limbs, redundant skin folds, narrow chest with short ribs, underdeveloped lungs, large head, curved thigh bones (type I), cloverleaf skull (type II)	Autosomal dominant; sporadic

FGFR3, fibroblast growth factor receptor 3.

^aCommonest mutation(s) is noted. Others may be documented.

^bVirtually all cases of thanatophoric dysplasia result from sporadic mutations because of its early lethality.