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Molecular Genetics Laboratory

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Craniosynostosis: Saethre-Chotzen Syndrome (TWIST1 Sequence, TWIST1 Deletion and FGFR3 P250R)

  • Synonyms: Muenke Syndrome, Coronal synostosis
  • LIS Mnemonic: MBSCSCRN


    Collect whole blood in a purple top (EDTA) tube (preferred). Extracted DNA is also acceptable.

    Volume Required

    5 ml whole blood or 2 ug extracted DNA

    Minimum Required

    3 ml whole blood


    Refrigerate sample until shipment. Send the sample at room temperature with overnight delivery for receipt Monday through Friday within 24 hours of collection.


    Whole blood can be refrigerated until shipment.

    Unacceptable conditions

    Heparinized specimens, severely hemolyzed specimens, frozen, clotted or possibly commingled specimens, blood in non-sterile or leaky containers, mislabeled or inappropriately labeled specimens.

    Specimen Handling

    Do not heat, freeze or centrifuge blood before shipment. Refrigerate sample until shipment.

Days Performed

Mon - Fri 9:00am to 4:00pm


4-6 weeks


81403, 81404

Disease Information

Clinical Features:

Craniosynostosis syndromes include Apert, Coronal Synostosis (Muenke's syndrome), Crouzon, Pfeiffer, and Saethre-Chotzen. These are highly penetrant, autosomal dominant disorders characterized by premature fusion of cranial sutures leading to an abnormal head shape, ocular hypertelorism with proptosis, midface hypoplasia, and the presence or absence of characteristic hand and/or foot manifestations. Although many cases are sporadic, familial cases have been reported. Due to variable expressivity of the phenotype, diagnosis based on clinical exam alone can be difficult; prenatal diagnosis based on ultrasound is unreliable. These disorders are due to mutations in fibroblast growth factor receptor genes (FGFR1, 2, 3) or the transcription factor TWIST. The FGFRs are a family of proteins with a simila structure that consist of three immunoglobulin-like extracellular domains, a transmembrane domain, and two tyrosine kinase domains. Mutations that cause craniosynostosis occur predominantly in the third Ig-like domain. Pfeiffer syndrome has been characterized by two phenotypes. A single common mutation, p.Pro252Arg, in the linker region between the second and third Ig-like domains of FGFR1 has been associated with a relatively mild form of Pfeiffer syndrome (type 1). The more severe form (type 2) with pronounced craniosynostosis and large thumbs and toes is due to mutations within the FGFR2 gene. Several syndromes, including Crouzon, Apert, and Pfeiffer are due to mutations in the fibroblast growth factor receptor, type 2 (FGFR2) gene on chromosome 10. These diseases represent the bulk of genetic conditions resulting in cranial dysmorphologies, Approximately 80% of FGFR2 mutations are missense mutations in exons 8 and 10. An additional 10% of mutations are located in exons 3, 5, 11, 14, 15, 16, and 17. The diagnosis of coronal synostosis syndrome is based on identification of the p.Pro250Arg mutation in FGFR3. The symptoms are extremely variable, but unilateral craniosynostosis is common. The classical phenotype described for Saethre-Chotzen syndrome is synostosis of the coronal sutures of the skull resulting in facial dysmorphologies including asymmetry to the face, hypertelorism and maxillary hypoplasia. Frequently, a high forehead with a low hairline, drooping eyelids, conductive deafness, cleft palate, deviated nasal septum and malocclusions are also present. Brachydactyly and cutaneous syndactyly between the second and third fingers and toes are also seen in the majority of cases. Mild to moderate mental retardation is often present. Both point mutations and deletions in the TWIST1 gene (7p21) have been identified in patients with Saethre-Chotzen syndrome. About one-half of the point mutations are insertions or deletions, and many of the remainder are missense or nonsense mutations. Between 10%-20% of cases are due to deletions of the entire gene.

Test Methods:

TWIST1: Sequence and deletion analysis of the coding region of the TWIST gene. Due to the phenotypic overlap between coronal synostosis and Saethre-Chotzen syndrome, analysis for the p.Pro250Arg mutation in the FGFR3 gene is included in the Saethre-Chotzen panel.

Related Tests:

FGFR1: Sequence analysis for the p.Pro252Arg mutation in the FGFR1 gene FGFR2: Level I FGFR2 Screen: Sequence analysis of exons 8 and 10. Level II FGFR2 Screen: Sequence analysis of exons 3, 5, 11, 14, 15, 16, and 17. Known mutation analysis is available to family members for mutations previously identified by sequence analysis or deletion/duplication analysis. Prenatal testing is available to individuals who are confirmed carriers of a mutation. Please contact the laboratory director to discuss appropriate testing prior to collecting a prenatal specimen.


Test results with interpretation will be mailed and/or faxed to the referring physician following completion of the test. Additional reports will be provided as requested.


The clinical utility of the assay is to support a clinical diagnosis of the disease, facilitate genetic counseling, assess the risk to other first degree relatives and to facilitate testing of at - risk family members.

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