Airway Growth in Preoperative Patients with Crouzon Syndrome.

Background: Obstructive sleep apnea is common in patients with Crouzon syndrome, yet it may be caused by multiple factors. This study aims to investigate the natural history of airway development in preoperative Crouzon patients, from infants to adults. Methods: Preoperative computed tomography (CT) scans (Crouzon syndrome, n = 73; control, n = 87) were divided into five age subgroups. CT scans were measured using Materialise software. Results: Before 6 months of age, nasal airway volume in patients with Crouzon syndrome was smaller than normal by 37% (p = 0.002), and the cross-sectional area at the choana reduced by 45% (p < 0.001). The reduction of nasal airway volume and cross-sectional area reached their nadir at 2 years of age, with shortening of 44% and 63% (both p < 0.001), respectively. They gradually caught up to normal dimensions after 6 years of age. Between 2 and 6 years, the pharyngeal airway in patients with Crouzon syndrome reduced 44% (p = 0.011) compared with controls. However, the airway cross-sectional area at condylion and gonion levels was less than normal, before 6 months (35%, p = 0.024) and (44%, p = 0.006) after 2 years of age, respectively. This reduction remains into adulthood. Conclusion: Nasal airway volume is more limited in children with Crouzon syndrome who are younger than 2 years of age. Whereas after 2 years of age, the pharyngeal airway develops significant volume restriction, leading to timing and specific treatment area foci based on the site of temporal maximal constriction.

C-type natriuretic peptide analog treatment of craniosynostosis in a Crouzon syndrome mouse model.

Activating mutations of fibroblast growth factor receptors (FGFRs) are a major cause of skeletal dysplasias, and thus they are potential targets for pharmaceutical intervention. BMN 111, a C-type natriuretic peptide analog, inhibits FGFR signaling at the level of the RAF1 kinase through natriuretic peptide receptor 2 (NPR2) and has been shown to lengthen the long bones and improve skull morphology in the Fgfr3Y367C/+ thanatophoric dysplasia mouse model. Here we report the effects of BMN 111 in treating craniosynostosis and aberrant skull morphology in the Fgfr2cC342Y/+ Crouzon syndrome mouse model. We first demonstrated that NPR2 is expressed in the murine coronal suture and spheno-occipital synchondrosis in the newborn period. We then gave Fgfr2cC342Y/+ and Fgfr2c+/+ (WT) mice once-daily injections of either vehicle or reported therapeutic levels of BMN 111 between post-natal days 3 and 31. Changes in skeletal morphology, including suture patency, skull dimensions, and long bone length, were assessed by micro-computed tomography. Although BMN 111 treatment significantly increased long bone growth in both WT and mutant mice, skull dimensions and suture patency generally were not significantly affected. A small but significant increase in the relative length of the anterior cranial base was observed. Our results indicate that the differential effects of BMN 111 in treating various skeletal dysplasias may depend on the process of bone formation targeted (endochondral or intramembranous), the specific FGFR mutated, and/or the specific signaling pathway changes due to a given mutation.

A model for the pharmacological treatment of crouzon syndrome.

OBJECTIVE: Crouzon syndrome is caused by mutations in fibroblast growth factor receptor 2 (FGFR2) leading to constitutive activation of receptors in the absence of ligand binding. The syndrome is characterized by premature fusion of the cranial sutures that leads to abnormal cranium shape, restricted brain growth, and increased intracranial pressure. Surgical remodeling of the cranial vault is currently used to treat affected infants. The purpose of this study was to develop a pharmacological strategy using tyrosine kinase inhibition as a novel treatment for craniosynostotic syndromes caused by constitutive FGFR activation. METHODS: Characterization of cranial suture fusion in Fgfr2 mutant mice, which carry the most common Crouzon mutation, was performed using micro-computed tomographic analysis from embryogenesis through maturation. Whole calvarial cultures from wild-type and Fgfr2 mice were established and cultured for 2 weeks in the presence of dimethyl sulfoxide control or PD173074, an FGFR tyrosine kinase inhibitor. Paraffin sections were prepared to show suture morphology and calcium deposition. RESULTS: In untreated Fgfr2 cultures, the coronal suture fused bilaterally with loss of overlap between the frontal bone and parietal bone. Calvaria treated with PD173074 (2 micromol/L) showed patency of the coronal suture and were without evidence of any synostosis. CONCLUSION: We report the successful use of PD173074 to prevent in vitro suture fusion in a model for Crouzon syndrome. Further studies are underway to develop an in vivo treatment protocol as a novel therapeutic modality for FGFR associated craniosynostotic syndromes.

The natural history of the Silver-Russell syndrome: a longitudinal study of thirty-nine cases.

The growth of 39 children with Silver-Russell syndrome has been followed for 1-13 years. Pregnancy and labor were normal; none of the 61 sibs had the syndrome. Height at referral (mean age 4.6 years) averaged 3.6 SD below the mean and remained at this level during subsequent growth. Bone age averaged 69 percent of normal at referral but caught up by puberty, which occurred at the normal time. Nineteen cases were treated with human growth hormone without lasting effect. There is no clear-cut distinction between the Silver and Russell syndromes; the name should be Silver-Russell. It is likely that some 10 percent of cases have birth weights in the minus 1.5 to minus 2.0 SD range.