Saethre-Chotzen syndrome

The estimated prevalence is 1 in 25,000–50,000 live births.

Saethre-Chotzen syndrome is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% risk of inheriting the pathogenic TWIST1 variant. A proportion of affected
individuals have a de novo pathogenic variant. In such cases, the parents are unaffected and the recurrence risk for future siblings is low but not zero because of the possibility of parental germline mosaicism. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis of Saethre-Chotzen syndrome is established in a proband with suggestive clinical findings and confirmed by the identification of a heterozygous germline pathogenic variant in the TWIST1 gene on molecular genetic testing. Craniofacial computed tomography is used to evaluate the pattern and extent of craniosynostosis when clinically suspected. Ophthalmologic examination, including assessment for papilloedema, supports detection of increased intracranial pressure.

Main differential diagnoses include:

• : uni- or bicoronal synostosis with frequent sensorineural hearing loss and variable developmental delay; FGFR3 (p.Pro250Arg).
• : craniosynostosis with marked proptosis and midface retrusion but without the characteristic ear anomalies and digital findings of Saethre-Chotzen syndrome; FGFR2.
• : craniosynostosis with broad, medially deviated thumbs and great toes and variable brachydactyly; FGFR1, FGFR2.
• : craniosynostosis with severe bilateral syndactyly of the hands and feet; FGFR2.
• TCF12-related craniosynostosis: uni- or bicoronal synostosis with variable expressivity and occasional developmental delay; TCF12.

• Genetic testing supports establishing the diagnosis by identifying the underlying pathogenic TWIST1 variant, clarifying the genetic aetiology and providing a basis for genetic counselling and predictive testing.
• A confirmed molecular diagnosis can inform condition-specific surveillance and multidisciplinary clinical management, including monitoring for known complications associated with Saethre-Chotzen syndrome.

• Gallagher ER, Ratisoontorn C, Cunningham ML. Saethre-Chotzen syndrome. 2003 May 16 [updated 2019 Jan 24]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: 20301368.
• Den Ottelander BK, Van Veelen MC, De Goederen R, Van De Beeten SD, Dremmen MH, Loudon SE, et al. Saethre-Chotzen syndrome: long-term outcome of a syndrome-specific management protocol. Dev Med Child Neurol. 2021;63(1):104-110. PMID: .
• Mathijssen IMJ; Working Group Guideline Craniosynostosis. Updated guideline on treatment and management of craniosynostosis. J Craniofac Surg. 2021;32(1):371-450. PMID: .