Heterozygous P250L mutation of fibroblast growth factor receptor 3 in a case of isolated craniosynostosis.

Craniosynostoses are caused by premature fusion of one or more sutures of the infant’s skull with an incidence between 1:1000 and 1:10 000. Isolated and syndromic forms can be differentiated and are involved in over 150 genetic disorders. Syndromic forms tend to be inherited and include variable other malformations of the extremities, the backbone, and the face. Isolated forms of craniosynostoses are often non-hereditary with closure of a single cranial suture. In most cases of syndromic craniosynostoses, multiple sutures are closed and often hydrocephalus and intracranial hypertension occurs. Mutations in the genes for fibroblast growth factor receptors (FGFR) 1, 2 , and 3 have been associated with syndromic craniosynostoses in a variety of clinical phenotypes (table 1). Muenke syndrome has been reported as syndromic craniosynostosis with unilateral or bilateral coronal synostosis, and minimal non-facial features. Muenke syndrome has been diagnosed in patients ascribed to different clinical entities, such as Saethre-Chotzen, Pfeiffer, Crouzon, and JacksonWeiss syndromes. In these cases, a specific single mutation P250R (749C→G) was found in the FGFR3 gene, first described by Bellus et al. Patients show variable abnormalities on radiographs of the hands and feet, including thimble-like middle phalanges, coned epiphyses, and carpal and tarsal fusions, and in some cases brachydactyly. Sensorineural hearing loss has been described in approximately 30% of cases and developmental delay has rarely been found. 5–7 The P250R mutation is located in the linker region between the second and third extracellular Ig-like domains of the FGFR3 protein. The corresponding residues are mutated in two other FGFRs involved in craniosynostoses syndromes, FGFR1 (P252R, Pfeiffer syndrome) and FGFR2 (P253R, Apert syndrome). Moloney et al pointed out that nucleotide position 749C has one of the highest mutation rates described in the human genome. In the most severely affected cases, bicoronal craniosynostosis was associated with hypertelorism and marked bulging of the temporal fossae has been found. P250R mutation is often familial and associated with a more severe phenotype in females than in males. A general conclusion given by many of the authors who screened craniosynostosis patients for mutations in FGFR3 was that isolated craniosynostosis patients should be tested for the P250R mutation, since variable clinical expression and minimal clinical signs are common features of this mutation.