Craniosynostosis syndromes

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Inclusion criteria:

  • Any combination of more than one major cranial vault suture fused at original presentation (from metopic, sagittal, left coronal, right coronal, left lambdoid, right lambdoid)
  • Single suture synostosis accompanied by either (a) dysmorphic features or at least one major extracranial abnormality; (b) significant learning disability; (c) first or second degree relative with craniosynostosis, or offspring of consanguineous union

Exclusion criteria:

  • Evidence of likely secondary cause. This is most likely to comprise (a) extreme prematurity <28 weeks’ gestation; (b) complications of severe perinatal asphyxia; (c) teratogenic exposure, most commonly sodium valproate; (d) compelling history of intrauterine growth restriction; (e) documented rickets (genetic or acquired)

Prior genetic testing guidance

  •  Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition.
  •  Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.

PLEASE NOTE: The sensitivity of WGS compared to current diagnostic genetic testing has not yet been established. It is therefore important that tests which are clinically indicated under local standard practice continue to be carried out.

Prior genetic testing genes
Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice:

  • Genome-wide copy number variation testing (e.g. aCGH, SNP array or other genomic microarray)
  • DNA sequencing of FGFR3-P250R, FGFR2 exons IIIa (8) and IIIc (10), TWIST1 exon 1 in all cases
  • Additional tests available for other genes as clinically indicated (nationally commissioned testing). These tests will most commonly include the EFNB1, ERF and TCF12 genes (mutations in each of these genes contribute ≥1% of craniosynostosis overall), and MLPA of TWIST1. Additional testing is currently offered for FGFR1, FGFR2 (extended screen), IL11RA, POR, RAB23 and ZIC1.

Closing statement

These requirements will be kept under continual review during the main programme and may be subject to change.

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