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2009 Annual Meeting Abstracts

The Natural History of Patients Treated for Saethre-Chotzen Syndrome
Roy Foo, MD1, Yifan Guo, BA2, Donna M. McDonald-McGinn, MS, CGC1, Elaine Zeckai, MD1, Linton A. Whitaker, MD1, Scott P. Bartlett, MD1.
1Children's Hospital of Philadelphia, Philadelphia, PA, USA, 2University of Pennsylvania School of Medicine, Philadelphia, PA, USA.

Saethre-Chotzen Syndrome (SCS) is an autosomal dominant craniofacial dysostosis syndrome caused by mutations in the TWIST1 gene with variable expression. It has a heterogeneous phenotypic presentation. Patients with SCS typically present to craniofacial clinics because of craniosynostosis--usually either uni- or bi-coronal. Other cranial sutures such as the metopic or the sagittal may be involved. The purpose of this study is to determine the natural history of patients with SCS, to follow the outcomes of their cranial vault remodeling operations, and to correlate clinical history and outcomes to specific genetic molecular diagnosis.
A retrospective chart review was performed on patients treated at the Children's Hospital of Philadelphia who have a genetic (TWIST1) diagnosis of SCS (n = 23) over a period of 23 years (1985 to 2008). Their phenotypic presentation (including type of craniosynostosis, facial features, auricular morphology, upper and lower limb dysmorphologies, and developmental delays), need for primary cranial vault remodeling surgery, subsequent need for re-operation were recorded. Genetic records were reviewed to identify each patient's specific TWIST1 gene mutation.
Forty-three percent of patients (n=10) were female, 57% (n=13) were male. Fifty-two percent of the patients (n=12) had bi-, 26% (n=6) had uni-, and 13% (n=3) had pan-craniosynostosis. One had metopic craniosynostosis and 1 had sagittal craniosynostosis. Our average length of follow-up was 7.6 years (range 1 month to 19.6 years).
Nineteen patients (83%) required cranial vault surgery. The remaining 4 patients did not require surgical intervention as their cranial vault dysmorphology was mild and they had no clinical evidence of increased intracranial pressures. No patients required surgical intervention for maxillary hypoplasia.
Of the 19 patients who required cranial vault operations, 8 patients, following the initial surgery, were found to require a repeat cranial vault remodeling procedure (Whitaker Class IV). One patient required a major re-operation less than the original intervention (Whitaker Class III). Two patients have required minor revisional procedures (Whitaker Class II) and four patients did not require further intervention (Whitaker Class I). The phenotypic presentation of these patients are summarized in Table 1. Table 2 correlates location of genetic mutation with phenotype and surgical outcome. Figure 1 represents a gene map which details the location of the TWIST1 gene mutations (each bar in the gene map represents a single patient in our series).
CONCLUSION: SCS, although autosomal dominant, has variable expression and a heterogeneic phenotypic presentation. The different locations of the TWIST1 gene mutation in this study did not correlate to a particular surgical outcome. Further long-term follow-up with accumulation of a larger series of patients is needed.

Table 1: Phenotypic Presentation of Patients Diagnosed with Saethre-Chotzen Syndrome
Phenotypic PresentationNumber of PatientsPercentage (%) of Patients
Low Frontal Hairline1461%
Facial Assymetry1357%
Downward Slanting Palpebral Fissure1670%
Depressed Nasal Bridge1252%
Prominent Crus Helicis1461%
Upper and Lower Extremity Anomalies (Syndactyly, Clinodactyly, Polydactyly)730%
Developmental Delay Requiring Intervention1043%
Systemic Anomalies (Co-arctation, Prolonged QT syndrome, Imperforate anus, DeGeorge Syndrome)417%

Table 2: Location of TWIST1 Gene Mutation with Clinical Correlation
Type of TWIST1 MutationTotal NumberSynostosisDevelopment DelayNeed for Cranial Remodeling ProcedureWhitaker Class IV
53 bicoronal, 2 unicoronal353
Upstream Domain71 pancraniosynostosis, 3 bicoronal, 2 unicoronal, 1 metopic052
DNA Binding Domain31 bicoronal, 2 unicoronal131
Helix 1 Domain32 pancraniosynostosis, 1 bicoronal220
Loop Domain33 bicoronal332


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