Craniosynostosis

Abstract

Craniosynostosis, defined as the premature fusion of the cranial sutures, presents many challenges in classification and treatment. At least 20% of cases are caused by specific single gene mutations or chromosome abnormalities. This article maps out approaches to clinical assessment of a child presenting with an unusual head shape, and illustrates how genetic analysis can contribute to diagnosis and management.

Figure 1

Diagnostic features of craniosynostosis. (a) Schematic diagram showing positions of the major cranial sutures. (b) CT scan (vertex view of skull) showing major sutures; anterior is at top. (c,d) Sagittal synostosis: note long, narrow head. (e,f) Metopic synostosis: note hypotelorism and triangular profile of forehead. (g,h) Bicoronal synostosis: broad, flattened head. (i,j) Right unicoronal synostosis: note flattened brow and anterior position of ear on affected side, deviation of nasal tip and prominent brow on unaffected side. (k–m), Congenital anomalies of feet or hands characteristic of Pfeiffer syndrome (k), Apert syndrome (l) and craniofrontonasal syndrome (m). (n) Crouzonoid facial appearance. (o) Severe hypertelorism, grooved nasal tip and left unicoronal synostosis in craniofrontonasal syndrome. (p) Ptosis and left unicoronal synostosis in Saethre-Chotzen syndrome. (q) Positional plagiocephaly: prominence on right anteriorly and left posteriorly, with right ear anterior and parallelogram shape to skull. (r) CT reconstruction showing left unicoronal synostosis. (s) CT reconstruction showing cloverleaf skull. (t) CT venogram showing abnormal venous drainage in multisuture syndromic craniosynostosis. See text for further details.

Figure 2

Distribution and types of mutation that commonly cause craniosynostosis. The major domains of the proteins encoded by the FGFR2 (a), FGFR3 (b), TWIST1 (c) and EFNB1 (d) genes are shown to scale, together with the position and types of mutation identified, and their associated phenotypes. Dashed line before EPH domain encoded by EFNB1 indicates 5′ untranslated region. The data, which were obtained from the Oxford cohort study, convey the relative prevalence of the most common mutations, but many rare mutations were absent in this survey. Asterisk indicates position of Ala391Glu mutation of FGFR3. crs, craniosynostosis. See text for information on protein domains.

Figure 3

Flow diagram for molecular genetic diagnosis of craniosynostosis, showing the minimum tests recommended for each clinical presentation. In practice, the Oxford laboratory bundles sequencing of the FGFR1, FGFR2 (exons IIIa and IIIc), FGFR3 and TWIST1 genes together into a single ‘level 1' screen to simplify the workflow. If the suggested tests are negative, the diagnosis should be reviewed.