Craniosynostosis diagnosis

Craniosynostosis diagnosis

Commonly, craniosynostosis is present at birth, but it is not always diagnosed when mild. Usually it is diagnosed as a cranial deformity in the first few months of life. The diagnosis relies on physical examination and radiographic studies, including plain radiography and computed tomography (CT). Clinical history should include complications of pregnancy, duration of gestation, and birth weight 1).

Premature fusion of the cranial sutures restricts cranial growth perpendicular to the affected suture with compensatory overgrowth along the other patent sutures. This results in the characteristic skull shape deformities noted in craniosynostosis. Diagnostic imaging is necessary to confirm the fused suture and to assess the accompanying skull deformities, intracranial pathology and other complications. A prematurely fused suture shows perisutural sclerosis, linearity, reduced serration, bony bridging or the absence of the suture on a plain skull radiography or CT image. Secondary signs of increased ICP, such as a “copper-beaten” appearance, are also observed in severe cases 2).

Soboleski et al. 3) reported the ultrasonographic findings of craniosynostosis as follows : 1) the loss of the hypoechoic fibrous gap between hyperechoic body plates; 2) an irregular, thickened inner sutural margin; 3) the loss of a beveled edge; and 4) asymmetric fontanels. On “Black Bone” MRI, the affected fused sutures are demonstrated as absence of suture 4).

A normal patent suture is demonstrated as a radiolucency, serrated and nonlinear line on plain skull radiography and 3D-CT images 5) 6) 7) 8).

Ultrasonography shows a normal patent suture as an uninterrupted hypoechoic fibrous gap between hyperechoic cranial bones with an end-to-end appearance on a transverse scan of the sagittal sinus and a beveled appearance on a transverse scan of the coronal and lambdoid suture9) 10) 11)

Conventional MRI has typically been unreliable in identifying sutures individually. However, Eley et al. described a novel gradient echo MRI sequence (“Black Bone”) that minimizes soft tissue contrast to enhance the bone-soft tissue boundaries and can demonstrate normal patent cranial sutures as hyperintensity distinguished from the signal void of the cranial bones 12).

Proisy et al. from Rennes first described a high-resolution sonography technique and its limitations. They then analyzed the reliabilityeffectiveness and role of ultrasonography in routine practice using a PubMed literature review.

Ten studies reported excellent correlations between ultrasonography and 3D-CT. Cranial US for the diagnosis of a closed suture had 100% sensitivity in 8 studies and 86-100% specificity before the age of 12 months. Negative findings mean imaging investigation can be stopped. If ultrasonography confirms diagnosis, neurosurgical consultation is required. Thus, 3D-CT can be postponed until appropriate before surgery.

Cranial suture ultrasound is an effective and reliable technique for the diagnosis of craniosynostosis. It has many advantages: it is fast and non-irradiating, and no sedation is required. It should be used as first-line imaging in infants below the age of 8-12 months when craniosynostosis is clinically suspected. 13).



Panchal J, Uttchin V. Management of craniosynostosis. Plast Reconstr Surg. 2003;111:2032–48.

Kim HJ, Roh HG, Lee IW. Craniosynostosis : Updates in Radiologic Diagnosis. J Korean Neurosurg Soc. 2016 May;59(3):219-26. doi: 10.3340/jkns.2016.59.3.219. Epub 2016 May 10. Review. PubMed PMID: 27226852; PubMed Central PMCID: PMC4877543.
3) , 11)

Soboleski D, Mussari B, McCloskey D, Sauerbrei E, Espinosa F, Fletcher A. High-resolution sonography of the abnormal cranial suture. Pediatr Radiol. 1998;28:79–82.
4) , 12)

Eley KA, Watt-Smith SR, Sheerin F, Golding SJ. “Black Bone” MRI : a potential alternative to CT with three-dimensional reconstruction of the craniofacial skeleton in the diagnosis of craniosynostosis. Eur Radiol. 2014;24:2417–2426.

Badve CA, K MM, Iyer RS, Ishak GE, Khanna PC. Craniosynostosis : imaging review and primer on computed tomography. Pediatr Radiol. 2013;43:728–742. quiz 725-727.

Branson HM, Shroff MM. Craniosynostosis and 3-dimensional computed tomography. Semin Ultrasound CT MR. 2011;32:569–577.

Kirmi O, Lo SJ, Johnson D, Anslow P. Craniosynostosis : a radiological and surgical perspective. Semin Ultrasound CT MR. 2009;30:492–512.

Nagaraja S, Anslow P, Winter B. Craniosynostosis. Clin Radiol. 2013;68:284–292.

Regelsberger J, Delling G, Helmke K, Tsokos M, Kammler G, Kränzlein H, et al. Ultrasound in the diagnosis of craniosynostosis. J Craniofac Surg. 2006;17:623–625. discussion 626-628.

Soboleski D, McCloskey D, Mussari B, Sauerbrei E, Clarke M, Fletcher A. Sonography of normal cranial sutures. AJR Am J Roentgenol. 1997;168:819–821.

Proisy M, Bruneau B, Riffaud L. How ultrasonography can contribute diagnosis of craniosynostosis. Neurochirurgie. 2019 Oct 2. pii: S0028-3770(19)30231-0. doi: 10.1016/j.neuchi.2019.09.019. [Epub ahead of print] PubMed PMID: 31586456.

Craniosynostosis pathophysiology

Craniosynostosis pathophysiology

Without adequate evaluation of pathophysiologycranial vault expansion shows limited ability to compensate intracranial hypertension, as long as there is persistence of other causative factors of the raised ICP, such as hydrocephalus, impairment of CSF circulation or venous sinus circulation and upper airway obstruction 1).

Reduced intracranial volume (ICV) and raised intracranial pressure (ICP) are assumed to be principal pathophysiological mechanisms in childhood craniosynostosis.

A study examined the association between ICV and ICP and whether ICV can be used to estimate the ICP.

Langvatn et al., analyzed ICV and ICP measurements from children with craniosynostosis without concurrent hydrocephalus and from age-matched individuals without craniosynostosis who underwent diagnostic ICPmeasurement.

The study included 19 children with craniosynostosis (mean age 2.2 ± 1.9 years) and 12 reference individuals without craniosynostosis (mean age 2.5 ± 1.6 years). There was no difference in ICV between the patient and reference cohorts. Both mean ICP (17.1 ± 5.6 mm Hg) and mean wave amplitude (5.9 ± 2.6 mm Hg) were higher in the patient cohort. The results disclosed no significant association between ICV and ICP values in the patient or reference cohorts, and no association was seen between change in ICV and ICP values after cranial vault expansion surgery (CVES) in 5 children in whom ICV and ICP were measured before and after CVES.

In this cohort of children with craniosynostosis, there was no significant association between ICV and ICP values prior to CVES and no significant association between change in ICV and ICP values after CVES in a subset of patients. Therefore, ICV could not reliably estimate the ICP values. The authors suggest that intracranial hypertension in childhood craniosynostosis may not be caused by reduced ICV alone but rather by a distorted relationship between ICV and the volume of intracranial content (brain tissue, CSF, and blood) 2).



Tamburrini G, Caldarelli M, Massimi L, Santini P, Di Rocco C. Intracranial pressure monitoring in children with single suture and complex craniosynostosis: a review. Childs Nerv Syst. 2005 Oct;21(10):913-21. Epub 2005 May 3. Review. PubMed PMID: 15871027.

Langvatn EA, Frič R, Due-Tønnessen BJ, Eide PK. Intracranial volume versus static and pulsatile intracranial pressure values in children with craniosynostosis. J Neurosurg Pediatr. 2019 Apr 19:1-9. doi: 10.3171/2019.2.PEDS18767. [Epub ahead of print] PubMed PMID: 31003225.

BBS9 gene in nonsyndromic craniosynostosis

BBS9 gene in nonsyndromic craniosynostosis

Mutations in several genes account for a small number of Nonsyndromic craniosynostosis (NCS) patients; thus, the molecular etiopathogenesis of NCS remains largely unclear.

In 2012 Justice et al., conducted, the first genome-wide association study for nonsyndromic sagittal craniosynostosis (sNSC) using 130 non-Hispanic case-parent trios of European ancestry (NHW). They found robust associations in a 120-kb region downstream of BMP2 flanked by rs1884302 (P = 1.13 × 10(-14), odds ratio (OR) = 4.58) and rs6140226 (P = 3.40 × 10(-11), OR = 0.24) and within a 167-kb region of BBS9 between rs10262453 (P = 1.61 × 10(-10), OR = 0.19) and rs17724206 (P = 1.50 × 10(-8), OR = 0.22). They replicated the associations to both loci (rs1884302, P = 4.39 × 10(-31) and rs10262453, P = 3.50 × 10(-14)) in an independent NHW population of 172 unrelated probands with sNSC and 548 controls. Both BMP2 and BBS9 are genes with roles in skeletal development that warranted functional studies to further understand the etiology of sNSC 1).

Sewda et al., identified a novel BBS9 variant that further shows the potential involvement of BBS9 in the pathogenesis of craniosynostosis (CS) 2)

A study of Barba et al., aimed at characterizing the molecular signaling implicated in the aberrant ossification of cranial sutures in NCS patients. Comparative gene expression profiling of NCS patient sutures identified a fused suture-specific signature, including 17 genes involved in primarycilium signaling and assembly. Cells from fused sutures displayed a reduced potential to form primary cilia compared to cells from control patent sutures of the same patient.

They identified specific upregulated splice variants of the Bardet Biedl syndrome-associated gene 9 (BBS9), which encodes a structural component of the ciliary BBSome complex. BBS9 expression increased during in vitro osteogenic differentiation of suture-derived mesenchymal cells of NCS patients. Also, Bbs9 expression increased during in vivo ossification of rat sutures. BBS9 functional knockdown affected the expression of primary cilia on patient suture cells and their osteogenic potential. Computational modeling of the upregulated protein isoforms (observed in patients) predicted that their binding affinity within the BBSome may be affected, providing a possible explanation for the aberrant suture ossification in NCS3).

Previous genome-wide association study of sagittal nonsyndromic craniosynostosis identified associations with variants downstream from BMP2and intronic in BBS9. Because no coding variants in BMP2 were identified, Justice et al., hypothesized that conserved non-coding regulatory elements may alter BMP2 expression. In order to identify and characterize noncoding regulatory elements near BMP2, two conserved noncoding regions near the associated region on chromosome 20 were tested for regulatory activity with a Renilla luciferase assay. For a 711 base pair noncoding fragment encompassing the most strongly associated variant, rs1884302, the luciferase assay showed that the risk allele (C) of rs1884302 drives higher expression of the reporter than the common allele (T). When this same DNA fragment was tested in zebrafish transgenesis studies, a strikingly different expression pattern of the green fluorescent reporter was observed depending on whether the transgenic fish had the risk (C) or the common (T) allele at rs1884302. The in vitro results suggest that altered BMP2 regulatory function at rs1884302 may contribute to the etiology of sagittal nonsyndromic craniosynostosis. The in vivo results indicate that differences in regulatory activity depend on the presence of a C or T allele at rs1884302 4).



Justice CM, Yagnik G, Kim Y, Peter I, Jabs EW, Erazo M, Ye X, Ainehsazan E, Shi L, Cunningham ML, Kimonis V, Roscioli T, Wall SA, Wilkie AO, Stoler J, Richtsmeier JT, Heuzé Y, Sanchez-Lara PA, Buckley MF, Druschel CM, Mills JL, Caggana M, Romitti PA, Kay DM, Senders C, Taub PJ, Klein OD, Boggan J, Zwienenberg-Lee M, Naydenov C, Kim J, Wilson AF, Boyadjiev SA. A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9. Nat Genet. 2012 Dec;44(12):1360-4. doi: 10.1038/ng.2463. Epub 2012 Nov 18. PubMed PMID: 23160099; PubMed Central PMCID: PMC3736322.

Sewda A, White SR, Erazo M, Hao K, García-Fructuoso G, Fernández-Rodriguez I, Heuzé Y, Richtsmeier JT, Romitti PA, Reva B, Jabs EW, Peter I. Nonsyndromic craniosynostosis: novel coding variants. Pediatr Res. 2019 Mar;85(4):463-468. doi: 10.1038/s41390-019-0274-2. Epub 2019 Jan 14. PubMed PMID: 30651579; PubMed Central PMCID: PMC6398438.

Barba M, Di Pietro L, Massimi L, Geloso MC, Frassanito P, Caldarelli M, Michetti F, Della Longa S, Romitti PA, Di Rocco C, Arcovito A, Parolini O, Tamburrini G, Bernardini C, Boyadjiev SA, Lattanzi W. BBS9 gene in nonsyndromic craniosynostosis: Role of the primary cilium in the aberrant ossification of the suture osteogenic niche. Bone. 2018 Jul;112:58-70. doi: 10.1016/j.bone.2018.04.013. Epub 2018 Apr 17. Erratum in: Bone. 2019 Apr;121:293. PubMed PMID: 29674126; PubMed Central PMCID: PMC5970090.

Justice CM, Kim J, Kim SD, Kim K, Yagnik G, Cuellar A, Carrington B, Lu CL, Sood R, Boyadjiev SA, Wilson AF. A variant associated with sagittal nonsyndromic craniosynostosis alters the regulatory function of a non-coding element. Am J Med Genet A. 2017 Nov;173(11):2893-2897. doi: 10.1002/ajmg.a.38392. Epub 2017 Oct 6. PubMed PMID: 28985029; PubMed Central PMCID: PMC5659764.
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