Craniosynostosis, caused by the premature fusion of one or more of the cranial sutures, can be classified into non-syndromic or syndromic and by which sutures are affected. Clinical assignment is a difficult challenge due to the high phenotypic variability observed between syndromes. During routine diagnostics, we screened 182 Spanish craniosynostosis probands, implementing a four-tiered cascade screening of FGFR2, FGFR3, FGFR1, TWIST1 and EFNB1. A total of 43 variants, eight novel, were identified in 113 (62%) patients: 104 (92%) detected in level 1; eight (7%) in level 2 and one (1%) in level 3. We subsequently screened additional genes in the probands with no detected mutation: one duplication of the IHH regulatory region was identified in a patient with craniosynostosis Philadelphia type and five variants, four novel, were identified in the recently described TCF12, in probands with coronal or multisuture affectation. In the 19 Saethre-Chotzen syndrome (SCS) individuals in whom a variant was detected, 15 (79%) carried a TWIST1 variant, whereas four (21%) had a TCF12 variant. Thus, we propose that TCF12 screening should be included for TWIST1 negative SCS patients and in patients where the coronal suture is affected. In summary, a molecular diagnosis was obtained in a total of 119/182 patients (65%), allowing the correct craniosynostosis syndrome classification, aiding genetic counselling and in some cases provided a better planning on how and when surgical intervention should take place and, subsequently the appropriate clinical follow up.

SummaryObjective. To review the results and complications of the surgical treatment of craniosynostosis in 283 consecutive patients treated between 1999 and 2007.Patients and methods. Our series consisted of 330 procedures performed in 283 patients diagnosed with scaphocephaly (n=155), trigonocephaly (n=50), anterior plagiocephaly (n=28), occipital plagiocephaly (n=1), non-syndromic multi-suture synostosis (n=20), and with diverse craniofacial syndromes (n=32; 11 Crouzon, 11 Apert, 7 Pfeiffer, 2 Saethre-Chotzen, and 2 clover-leaf skull). We used the classification of Whitaker et al. to evaluate the surgical results. Complications of each technique and time of patients' hospitalization were also recorded. The surgeries were classified in 12 different types according to the techniques used. Type I comprised endoscopic assisted osteotomies for sagittal synostosis (42 cases). Type II included sagittal suturectomy and expanding osteotomies (46 cases). Type III encompassed procedures similar to type II but that included frontal dismantling or frontal osteotomies in scaphocephaly (59 cases). Type IV referred to complete cranial vault remodelling (holocranial dismantling) in scaphocephaly (13 cases). Type V belonged to fronto-orbital remodelling without fronto-orbital bandeau in trigonocephaly (50 cases). Type VI included fronto-orbital remodelling without fronto-orbital bandeau in plagiocephaly (14 cases). In Type VII cases of plagiocephaly with frontoorbital remodelling and fronto-orbital bandeau were comprised (14 cases). Type VIII consisted of occipital advancement in posterior plagiocephaly (1 case). Type IX included standard bilateral fronto-orbital advancement with expanding osteotomies (30 cases). Type X was used in multi-suture craniosynostosis (15 cases) and consisted of holocranial dismantling (complete cranial vault remodelling). Type XI included occipital and suboccipital craniectomies in multiple suture craniosynostosis (10 cases) and Type XII instances of fronto-orbital distraction (26 cases).Results. The mortality rate of the series was 2 out of 283 cases (0.7%). These 2 patients died one year after surgery. All complications were resolved without permanent deficit. Mean age at surgery was 6.75 months. According to Whitaker et al's classification, 191 patients were classified into Category I (67.49%), 51 into Category II (18.02%), 30 into Category III (10.6%) and 14 into Category IV (4.90%). Regarding to craniofacial conformation, 85.5 % of patients were considered as a good result and 15.5% of patients as a poor result. Of the patients with poor results, 6.36% were craniofacial syndromes, 2.12% had anterior plagiocephaly and 1.76% belonged to non-syndromic craniosynostosis.The most frequent complication was postoperative hyperthermia of undetermined origin (13.43% of the cases), followed by infection (7.5%), subcutaneous haematoma (5.3%), dural tears (5%), and CSF leakage (2.5%). The number of complications was higher in the group of re-operated patients (12.8% of all). In this subset of reoperations, i...

SummaryObjective. To review the results and complications of the surgical treatment of craniosynostosis in 283 consecutive patients treated between 1999 and 2007.Patients and methods. Our series consisted of 330 procedures performed in 283 patients diagnosed with scaphocephaly (n=155), trigonocephaly (n=50), anterior plagiocephaly (n=28), occipital plagiocephaly (n=1), non-syndromic multi-suture synostosis (n=20), and with diverse craniofacial syndromes (n=32; 11 Crouzon, 11 Apert, 7 Pfeiffer, 2 Saethre-Chotzen, and 2 clover-leaf skull). We used the classification of Whitaker et al. to evaluate the surgical results. Complications of each technique and time of patients' hospitalization were also recorded. The surgeries were classified in 12 different types according to the techniques used. Type I comprised endoscopic assisted osteotomies for sagittal synostosis (42 cases). Type II included sagittal suturectomy and expanding osteotomies (46 cases). Type III encompassed procedures similar to type II but that included frontal dismantling or frontal osteotomies in scaphocephaly (59 cases). Type IV referred to complete cranial vault remodelling (holocranial dismantling) in scaphocephaly (13 cases). Type V belonged to fronto-orbital remodelling without fronto-orbital bandeau in trigonocephaly (50 cases). Type VI included fronto-orbital remodelling without fronto-orbital bandeau in plagiocephaly (14 cases). In Type VII cases of plagiocephaly with frontoorbital remodelling and fronto-orbital bandeau were comprised (14 cases). Type VIII consisted of occipital advancement in posterior plagiocephaly (1 case). Type IX included standard bilateral fronto-orbital advancement with expanding osteotomies (30 cases). Type X was used in multi-suture craniosynostosis (15 cases) and consisted of holocranial dismantling (complete cranial vault remodelling). Type XI included occipital and suboccipital craniectomies in multiple suture craniosynostosis (10 cases) and Type XII instances of fronto-orbital distraction (26 cases).Results. The mortality rate of the series was 2 out of 283 cases (0.7%). These 2 patients died one year after surgery. All complications were resolved without permanent deficit. Mean age at surgery was 6.75 months. According to Whitaker et al's classification, 191 patients were classified into Category I (67.49%), 51 into Category II (18.02%), 30 into Category III (10.6%) and 14 into Category IV (4.90%). Regarding to craniofacial conformation, 85.5 % of patients were considered as a good result and 15.5% of patients as a poor result. Of the patients with poor results, 6.36% were craniofacial syndromes, 2.12% had anterior plagiocephaly and 1.76% belonged to non-syndromic craniosynostosis.The most frequent complication was postoperative hyperthermia of undetermined origin (13.43% of the cases), followed by infection (7.5%), subcutaneous haematoma (5.3%), dural tears (5%), and CSF leakage (2.5%). The number of complications was higher in the group of re-operated patients (12.8% of all). In this subset of reoperations, i...

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Craniosynostosis is the premature fusion of one or more sutures of the skull, which can be syndromic or isolated. Mutations in FGFR1, FGFR2, or FGFR3, among others, are often responsible for these syndromic cases. The associated of FGFR3 mutations with craniosynostosis has been restricted to three mutations, the common p.Pro250Arg in Muenke syndrome, p.Ala391Glu in Crouzon syndrome with acanthosis nigricans, and p.Pro250Leu identified in a family with isolated craniosynostosis. Other FGFR3 mutations result in various skeletal dysplasias: achondroplasia, hypochondroplasia, and thanatophoric dysplasia. Here, we report a novel mutation in exon 8 (IIIc) of FGFR3, p.Ala334Thr, in a young boy with mild craniosynostosis. The mutation segregated with mild craniosynostosis in the family and was absent in 188 normal controls. Alanine 334 is evolutionarily conserved in vertebrates and is located at the amino terminus of the βF loop in the FGFR3c isoform. The mutation is predicted to alter the protein tertiary structure which may impair its binding to its ligand, FGF1. The identification of a mutation in these clinically heterogeneous disorders can aid recurrence risk assessments. Although the implementation of a stepwise screening strategy is useful in diagnostics, mutations in unscreened regions of genes associated with craniosynostosis may explain a small proportion of craniosynostosis cases.