Abstract
Advances in molecular studies have shown that mutations in the fibroblast growth factor receptor (FGFR) genes are responsible for six autosomal dominant craniosynostosis syndromes. Each FGFR has a common structure which includes a conserved sequence that is thought to be critical for FGF binding. Mutations in this conserved region have been identified in FGFR1, 2, and 3 and have been associated with classic craniosynostosis syndromes, such as Pfeiffer and Apert syndromes. Recently, a new craniosynostosis syndrome has been described. This new syndrome is associated with a P250R mutation within the conserved region of FGFR3. This syndrome is characterized by synostosis (bilateral and unilateral); macrocephaly in the absence of synostosis; abnormalities of hands and feet, including broad big toes, brachydactyly, thimble-like middle phalanges, coned epiphyses, and carpal and tarsal fusions; sensorineural hearing loss; and developmental delay and/or mental retardation. To further expand the phenotype of this specific mutation, we describe a six-month-old male infant with a P250R FGFR3 mutation and Chiari I malformation.
Our patient was born at 37 weeks gestation with a birth weight of 5 lb. 9 oz. (15th percentile for 37 weeks) and length of 18.75 inches (50th percentile for 37 weeks). By six months of age, the patient's height and weight were below the 5th percentile, while his OFC remained in the normal range. The patient's features include FTT; hypotonia; a large, patent anterior fontanelle; generous thumbs and great toes; high arched palate, right parieto-occipital plagiocephaly; prominent occiput; asymmetric mandible: low set and posteriorly rotated ears; and flat nasal bridge. A skeletal survey was normal. Head MRI revealed flattening of the right occipital skull with no evidence of definite synostosis (CT scan of head has not been performed). The MRI study also revealed a Chiari I malformation. Subsequent molecular testing for the FGFRs indicated a P250R mutation of FGFK3. The patient's mother had congenital hydrocephalus and placement of a V-P shunt. She also had learning problems in school. Molecular testing on the mother also indicated a P250R mutation of FGFR3. In addition, the patient's maternal grandmother is reported to have a large head size with hydrocephalus.
Our case serves to further broaden the spectrum of the newly described craniosynostosis syndrome associated with the P250R mutation of FGFR3. Although many of the features present in this case have already been documented, to our knowledge, the finding of Chiari I malformation, has not been described and further expands the phenotype of this syndrome.
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Tenny, L., Allen, W., Schaefer, F. et al. Chlari I malformation associated with a P250R mutationv of FGFR3. Genet Med 2, 88 (2000). https://doi.org/10.1097/00125817-200001000-00135
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DOI: https://doi.org/10.1097/00125817-200001000-00135