Craniosynostosis is the premature ossification and fusion of one or more cranial sutures. It is one of the most common craniofacial anomalies, occurring in one in 2,000-2,500 births (Boulet, Rasmussen, & Honein, 2008). The multifactorial etiology of craniosynostosis involving both genetic and environmental factors results in a heterogeneous group of disorders (Heuze, Holmes, Peter, c Denominator represents those with phenotypic features described. ITTLEMAN ET AL. | 489 and maxilla-facial computed-tomography (CT) scans revealed metopic craniosynostosis while his alkaline phosphatase levels were low (49, Normal 129-291 U/L). ALPL gene sequencing confirmed the clinical suspicion of hypophosphatasia (HPP) (compound heterozygous c.526G>A/c.1250A>G, p.(Ala176Thr)/p.(Asn417Ser)) and CVR was performed at 18 months of age prior to initiation of enzyme replacement therapy. Craniosynostosis is a known feature of HPP, particularly the infantile type (Mornet, 2007). Individual CS#50 was first evaluated in the neonatal period for craniofacial dysmorphism and skeletal anomalies. Radiographic images documented markedly advanced bone age, widening of the proximal and middle phalanges, and severe cervical spinal stenosis. This patient underwent CVR for sagittal suture synostosis and posterior laminectomies of C3-C4 for cervical stenosis at 2 and 4 years of age, respectively. Over time, the patient was noted to have a flat midface, prominent forehead, full lips, and shallow orbits. The clinical diagnosis of Marshall-Smith syndrome was made and while molecular cytogenetic microarray was normal, sequencing of the NFIX gene could not be conducted. Craniosynostosis was reported in 5/38 (13%) of patients with Marshall-Smith syndrome in a previous study (Shaw et al., 2010).The implications of genetic testing have impact on the surgeon's discussion with the family prior to discussing surgical repair. It is well known, for example, that children with syndromic craniosynostosis tend to have higher relapse rates of their cranial dysmorphology, increased intra-cranial pressure and higher re-operative rates that their non-syndromic cohorts (Esparza et al., 2008;McCarthy et al., 1995). In agreement with a previous report of a large cohort of children with surgically repaired craniosynostosis, in this study, when comparing individuals with proven syndromic craniosynostosis to all others, there was a higher rate of multiple sutures affected (70 vs. 17%, p = < 0.000001) and need for several surgical procedures (48 vs. 25%, p = < 0.05), most of which were invasive ( Supplementary Table S3) (Wilkie et al., 2010). Likewise, the overall rates of suspicion for syndromic craniosynostosis (56/139, 40%) and identified underlying genetic diagnoses (27/56, 48%) are comparable to previous data by Wilkie et al. (2010) of 37% (122/326) and 60% (73/122), respectively. The present study does have some limitations. While a systematic evaluation was conducted by the initial provider evaluating the individual with craniosynostosis, a genetic evaluation was not ...