(29) Delayed-Onset Multisuture Craniosynostosis in TWIST1-Associated Saethre-Chotzen Syndrome: Case Report and Review of Atypical Phenotypic Progression

Background: Saethre-Chotzen Syndrome (SCS) is a rare disorder caused by pathogenic variants in TWIST1, a gene critical to craniofacial development and mesodermal differentiation.

Objectives: While SCS usually presents with coronal suture synostosis and characteristic craniofacial features at birth, phenotypic expression is highly variable. Here, we present a male patient with a de novo heterozygous nonsense TWIST1 variant and atypical SCS features.

Design/Methods: Full poster includes a literature review of prior reported cases, genotype, phenotype and outcomes, and compares and contrasts this atypical case to the known literature.

Results: The patient was initially evaluated in the Genetics Clinic at 2 weeks of age due to concerns for multiple congenital anomalies, including distinct facial features and mild pelvocaliectasis. Exam findings found distinct dysmorphic features, including bilateral blepharophimosis, prominent epicanthic folds, and bilateral single palmar creases. A follow-up genetics visit at 6 months of age revealed no concerns for developmental delays. Exome sequencing completed at ten months of age identified a de novo pathogenic variant in TWIST1, c.309C>A, p.(Tyr103Ter), felt likely to explain the findings of blepharophimosis and raised the concern for SCS. A head CT at 11 months of age revealed only metopic synostosis, not the expected SCS phenotype of coronal craniosynostosis. A follow-up head CT at three years of age revealed newly identified sagittal suture fusion and mild dolichocephaly. This finding conferred a diagnosis of multisuture craniosynostosis, still atypical for SCS, but a diagnosis of atypical SCS was thus conferred.

Conclusions: Although his cranial and neurological development remained stable, his progressive suture involvement raised concern for future progression to increased intracranial pressure; therefore, cranial vault reconstruction was recommended. This case highlights the progressive nature of SCS, demonstrating that normal imaging and head growth metrics early in life do not preclude the development of significant cranial pathology. In addition, this case supports the need to longitudinally monitor individuals with pathogenic TWIST1 variants using serial imaging, even in the absence of early skull deformities. Inadequate recognition and surveillance of atypical manifestations of SCS may result in delayed intervention and heightened risk for complications with pathologic sequelae.