An Overview of Craniosynostosis

Alex A. Kane, MD

The purpose of this review is to give an overview of craniosynostosis, targeted for the nonsurgeon, with emphasis on those aspects of craniosynostosis that could be of interest to the clinician treating deformational plagiocephaly. In particular, the orthotist could be involved in the treatment of both nonsynostotic deformational plagiocephaly and craniosynostosis by providing a cranial molding orthosis in both of these distinct clinical entities. The nomenclature applied in the description of these entities can lead to confusion with regard to diagnosis. Other articles in this themed issue describe in detail the treatment of deformational plagiocephaly. The focus here is on the epidemiology, pathogenesis, natural history, and surgical treatment of craniosynostosis. Differentiation of craniosynostosis from nonsynostotic deformational plagiocephaly is important, and methods to distinguish these entities are discussed as appropriate.

CRANIOSYNOSTOSIS

DEFINITIONS

Authoritative definitions of key terms in this subject such as "suture" and "craniosynostosis" are elusive. Nevertheless, commonly used working definitions of these terms are available. "Suture" is used to describe a fibrous articulation between adjacent bones. "Craniosynostosis" in its common use denotes the premature closure of one or more sutures. This conception implies that a schedule of expected sutural closure exists and that each suture eventually closes. ¹ In fact, the only suture that is known to routinely close in childhood is the metopic, which closes normally by the third year of life; all other cranial sutures begin to close at age 20 years or more. ² The term "closure" is also problematic. Although sutural "maturation" describes distinct histologic patterns of change noted with advancing age (such as increasing interdigitations), ² experts seem reticent to assert that the normal fate of a suture is for it to "close," ie, with bone obliterating the space between adjacent bones previously occupied by fibrous connective tissue. For most purposes, it is understood that craniosynostosis implies osseous bridging of the space between adjacent bones and loss of the ability for the bones to grow in a direction perpendicular to the affected suture.

It is important to distinguish between "isolated" or "nonsyndromic" craniosynostosis and "syndromic" craniosynostosis. The former implies a sporadically occurring problem that usually affects a single suture, causing a characteristic pattern of skull deformity ( Figure 1 ). Sagittal synostosis is associated with a scaphocephalic ("boat") head shape with elongation in the anteroposterior dimension. Metopic synostosis is associated with a trigonocephalic ("triangle shape") appearance with a frontal keel and is frequently seen with hypotelorism. Bilateral coronal synostosis is associated with a brachycephalic head shape, foreshortened in the anteroposterior dimension and widened in the transverse dimension. A skewed, or plagiocephalic head shape can be associated with either unilateral coronal synostosis (UCS) or unilateral lambdoid synostosis (ULS). Of course, the most common presentation of a patient with plagiocephaly involves no synostosis at all, which has in the past decade been termed "deformational" or "nonsynostotic" plagiocephaly.

Craniosynostosis syndromes involve a pattern of craniosynostosis in multiple sutures, which often have a known inheritance pattern and are also often associated with a characteristic pattern of limb deformities. These include the acrocephalosyndactyly syndromes of Apert, Pfeiffer, and Saethre-Chotzen. Surgeons often use the term "craniofacial dysostosis" to describe any syndrome with craniosynostosis, midface hypoplasia, and a dysmorphic cranial base. ²

EPIDEMIOLOGY

The birth prevalence of nonsyndromic craniosynostosis is estimated to be three to five per 10,000 births. ² Estimates of the relative frequencies of the different types of nonsyndromic synostoses vary. Cohen ³ reviewed the types, frequencies, and gender ratios of three large series of synostoses. If one includes only the contributions to these studies from isolated sagittal, coronal, metopic, and coronal synostoses, then sagittal synostosis represents 64% of all cases, followed by 28% for coronal, 5% for metopic, and 3% for lambdoid synostosis ( Figure 2 ). The birth prevalence of syndromic synostosis is significantly lower, estimated in the range of 0.15 per 10,000 births. ²

PATHOGENESIS

The pathogenesis of nonsyndromic craniosynostosis is largely unknown. There are several general theories of causation. ^4,5 Virchow surmised that the primary defect was within the suture, which then was translated to the cranial base by an unknown mechanism. ⁶ The theory promulgated by Moss ⁷ postulates that the cranial base is the source of the primary defect, which translates its effects on the suture through the dura mater. More recently, the dura has been the focus of much attention and is thought by many to play an integral role in determining the patency of the overlying suture. Still others believe that there is evidence to suggest that the developing brain itself has a primary role in production of the craniosynostosis phenotype. ⁸

In contrast to nonsyndromic craniosynostosis, significant progress has been made in localizing specific genetic pathways related to the pathogenesis of syndromic craniosynostosis. In the autosomal-dominant Crouzon and Apert syndromes, dozens of mutations have been found in fibroblast growth factor receptors, which are a family of transmembrane receptor tyrosine kinase proteins. ⁹ These same receptors are known to be mutated in a minority of all synostosis cases. Saethre-Chotzen syndrome is known to be associated with mutations in the TWIST gene, and Boston-type craniosynostosis is associated with mutations of the homeobox gene MSX2. ² Although much work is being done in this area, it will be some time before the complex biochemical and morphogenetic pathways leading from genetic mutation to the clinical phenotype are well understood.

COMPARATIVE DYSMORPHOLOGY OF NONSYNDROMIC CRANIOSYNOSTOSIS

SAGITTAL SYNOSTOSIS

Sagittal synostosis is the most common form of nonsyndromic synostosis. In one large series, a birth prevalence of 1.9 per 10,000 was noted, with a 6% frequency of familial pedigrees. ² Morphologically, when compared with unaffected skulls, there is a clear elongation anteroposteriorly and a narrowing bitemporally. The cranial base appears symmetric in the transverse dimension. ¹⁰ There is variability of the presenting deformity in sagittal synostosis with frequent use of such descriptive terms as "bulges, bosses, and bullets" applied to the skull shape, although the etiology of this heterogeneity is unclear. ¹¹ A common method for the overall description of the severity of deformity in sagittal synostosis is to calculate the cranial index, which is simply the cranial width divided by cranial length multiplied by 100. This simple index can be calculated using lengths and widths obtained either anthropometrically or from surface reformations from computed tomography (CT) scans. The mean preoperative cephalic index in sagittal synostosis is approximately 67%. ¹² More rigorous landmark-based analyses of the morphologic differences between sagittal synostosis skulls and normals have been performed. ¹³

METOPIC SYNOSTOSIS

Metopic synostosis is relatively rare and must be differentiated from the relatively common presence of a metopic ridge, which is a benign condition for which no surgical treatment is usually offered because simple metopic ridging is thought to be self-correcting. ² In contrast, metopic synostosis results in a triangular "keel" in the frontal bone, orbital hypotelorism, bitemporal narrowing, and biparietal widening and is not self-correcting. ¹⁴ There is evidence to suggest that patients with metopic synostosis could be particularly vulnerable to mental retardation when compared with the other forms of nonsyndromic craniosynostosis. ¹⁵

UNILATERAL CORONAL SYNOSTOSIS

The typical facies and osseous dysmorphology of patients with unilateral synostosis of a single coronal suture are important to distinguish from the other causes of plagiocephaly. On the side ipsilateral to the synostosis, the superior orbital rim is heightened and the orbital aperture is vertically elongated (the "harlequin" deformity). The ear position is anterior and lower, and the malar eminence is anteriorly positioned. The chin is contralaterally deviated. There is a deviation of the anterior cranial fossa toward the side of the synostosis with an average deviation of approximately 15°. There is decreasing asymmetry in the cranial fossae moving anteriorly to posteriorly. There are distinctive anatomic changes in the floor of the anterior fossa, which forms the orbital roof that can be appreciated on serial coronal cuts through the anterior cranial fossa. On the side ipsilateral to the synostosis, the floor of the anterior fossa rises without making an arch, and it rises to a higher level than the other side. The comparative endocranial base morphologies in the various types of plagiocephalies, including coronal and lambdoid synostosis, and deformational plagiocephaly have been studied and are distinctive. ¹⁶ Deflection off of the sagittal midline is minimal in deformational plagiocephaly, although it is significant in the synostotic etiologies. In terms of fossa sizes, the anterior fossa is small in UCS, with normal posterior fossa, as already described. This is different from the appearance in lambdoid synostosis, with the greatest asymmetry occurring in the posterior fossa, exhibiting contraction on the synostotic side and a relatively normal anterior fossa. In deformational plagiocephaly, there is relative symmetry of the fossa sizes. There is a characteristic orbital dysmorphology in UCS. ¹⁷ The anterior orbit contralateral to the synostosis in UCS is shortened vertically and/or elongated horizontally when compared with normals. There is also a characteristic mandibular dysmorphology associated with UCS, which is distinct from that found in ULS and deformational plagiocephaly. ¹⁸

LAMBDOID SYNOSTOSIS

Lambdoid synostosis is controversial, because it is widely thought that the term has been misapplied to deformational plagiocephaly, ¹⁹ and, consequently, there has been unnecessary surgical treatment for the latter. The incidence of lambdoid synostosis is the lowest of all the nonsyndromic synostoses. The exact incidence of lambdoid synostosis is not known, and is unlikely to be known, given the historical tendency to either confuse this clinical entity with, or not separate it fully from, nonsynostotic plagiocephaly. This is where the controversy comes in, because the gold standard for diagnosis of lambdoid synostosis is a pathology report showing histologic evidence of bony fusion. Because this evidence is not available preoperatively, other means are required to distinguish these entities clinically and radiographically. It is important to note that although surface reformations of high-resolution CT have become invaluable in the diagnosis of craniosynostosis, it is not perfectly sensitive in this regard. In particular, the plane of data acquisition (which is normally the axial plane) is of significance. If the plane of acquisition is parallel, or near parallel to the suture, the suture will appear to be synostotic. ²⁰ This phenomenon can confound the diagnosis of lambdoid synostosis because the lambdoid sutures are often running at an angle nearly parallel to the usual transverse plane of acquisition. An example of this is illustrated in Figure 3 , in which the same child appeared to have synostosis in one scan and an open suture in a subsequent scan taken with a different plane of acquisition.

As previously mentioned, endocranial base views can help confirm the diagnosis, because deflection of the midline would be expected in lambdoid synostosis, whereas it would not be expected in deformational plagiocephaly, and in lambdoid synostosis, the locus of asymmetry is in the posterior fossa.

Many reports have aimed to define distinguishing clinical characteristics between lambdoid synostosis and deformational plagiocephaly. ^21–24 In lambdoid synostosis, there is an occipitomastoid boss ipsilateral to the synostosis. The ear ipsilateral to the synostosis is inferiorly positioned and there is a cant to the skull base sloping downward on this side, which are both evident when viewed posteriorly. There are distinctive patterns of skull shapes in deformational plagiocephaly and lambdoid synostosis on both vertex and posterior views. ²¹ The idea here is that on vertex view in lambdoid synostosis, the skull is trapezoid-shaped, whereas deformational plagiocephaly is more parallelogram-shaped. This situation reverses when viewing the skulls from behind, with a more parallelogram shape in lambdoid synostosis and a more trapezoid shape in deformational plagiocephaly.

SURGICAL TREATMENT

Surgical management of craniosynostosis began with removal of the synostotic suture in a procedure known as "strip craniectomy." The rationale for surgical intervention included three hypotheses ¹ : 1) failure to remove the synostosis would lead to dire consequences, including hydrocephalus, blindness, mental retardation, and premature death; 2) removal of the synostosis would allow normal cranial growth and development; and 3) maintenance of the suturectomy site as a nonossified zone into childhood was necessary for normal cranial growth and development. Over time, reossi- fication at the site of suturectomy became problematic, leading to interventions that included repeat ostectomy, adding chemical agents to the dura to prevent reossification, or addition of mechanical barriers of alloplastic materials to prevent this problem. There seems to have been a gradual shift away from the practice of strip craniectomy toward the practice of calvarial vault remodeling, although reliable statistics regarding practices of neurosurgeons and plastic surgeons who perform this procedure, either jointly or independently, are not readily available. There is evidence that better correction of endocranial base morphology occurs after subtotal calvarial vault remodeling for sagittal craniosynostosis than with strip craniectomy ¹² ; however, photographic assessment by lay and professional observers has shown no advantage of one technique over the other. ²⁵ There are many variations in surgical technique for calvarial vault reconstruction and frontoorbital advancement, which are the mainstays of treatment for craniosynostosis. These variations are largely dependent on the surgeon's preference and training, and not usually on evidence-based outcomes studies. Recently, two newer surgical technologies have been adapted to treat craniosynostosis, including endoscopic-assisted surgery and bone distraction. A standard extended strip craniectomy performed with endoscopic assistance, combined with postextirpative calvarial molding helmet therapy, has been advocated as a less morbid management for craniosynostosis. ^1,26 Reported outcomes are satisfactory, but long-term outcomes are not yet available. Some surgeons use cranial molding orthoses after conventional, open operative approaches for treatment of synostosis. ²⁷

In addition to method of treatment, the timing of intervention is controversial, without much scientific evidence to support early surgical treatment in infancy versus late treatment. Practitioners who prefer early intervention (eg, before 6 months of age) do so for several reasons, believing that the operation is technically easier secondary to the plasticity of the calvaria, the osseous defects created by cranial vault reconstruction are more reliably healed with earlier treatment, and the morphologic results will be superior. Others believe surgery should be delayed until a year or more of life, thinking that operating on more mineralized bone present at that age will prevent recurrence of the deformity.

Increased intracranial pressure in children with nonsyndromic synostosis has been reported and has been assumed to affect mental development. ^28,29 A number of studies have suggested that children with nonsyndromic craniosynostosis are at increased risk for learning disorders and mental retardation, regardless of whether surgery is performed. ¹⁵ There has been considerable debate regarding the hypothesis that surgical treatment of single-suture craniosynostosis prevents retardation or improves global cognitive functioning at a later age. At present, multicenter studies are ongoing to better elucidate this question, but current opinion seems to find little support for the contention that surgery is therapeutic in this regard. ¹⁵

Few studies have reported on the long-term morphologic outcomes of surgically treating versus not treating craniosynostosis. In one study of untreated UCS, ³⁰ there were measurable and significant differences in facial morphology between patients with untreated UCS and normal skulls, but not enough patients were available to decide definitively whether the dysmorphology of untreated unilateral coronal synostosis is quantitatively consistent over time, (ie, whether the dysmorphology normalizes or deteriorates with growth). A subsequent study used this group of untreated patients as a comparison group with another group of patients who had UCS treated in infancy who returned for evaluation at dentoskeletal maturity. ³¹ The results suggested a significant reversion toward the untreated phenotype over time when comparing short-term postoperative CT scans with the ones performed at dentoskeletal maturity.

AN ALGORITHM FOR TREATMENT OF A CHILD WITH DYSMORPHIC CALVARIA

A complete history and physical examination is performed, assisted in the differential diagnosis by the aforementioned clinical signs. ^32,33 If torticollis is discovered, appropriate physical therapy is initiated, with sternocleidomastoid release very rarely required. Routine skull radiographs are performed. If deformational plagiocephaly is diagnosed, and if the child is less than 1 year of age, a cranial molding orthosis is offered. If the child is older than 1 year, the option exists for surgical calvarial remodeling, but this is performed increasingly rarely and only in the most severe cases. If there is reason to suspect craniosynostosis, from radiographic and/or clinical examination, a high-resolution CT scan is performed with surface reformations. (If this is done to rule out lambdoid synostosis, attention must be paid to the plane of data acquisition, as previously mentioned.) If synostosis is diagnosed, appropriate surgical treatment is recommended, usually before 6 months of age, with the technique varying with respect to the affected portions of the calvaria or orbits.

CONCLUSION

The treatment of craniosynostosis is complicated by incomplete information regarding its pathogenesis and pathophysiology, natural history, and treatment. The functional impairments that could be inherent to the condition are not well characterized, and there have been no randomized, controlled studies comparing outcomes from different treatment approaches.

Correspondence to: Alex A. Kane, MD, Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis Children's Hospital, 1 Children's Place, Suite 11W7, St. Louis, MO 63110; e-mail: kanea@wustl.edu .

ALEX A. KANE, MD, is affiliated with the Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO.

References:

Marsh JL, Kane AA, Gurley JM. Non-syndromic craniosynostosis. Plastic Surgery. Philadelphia: WB Saunders; 2004.
Cohen MM, MacLean RE, eds. Craniosynostosis: Diagnosis, Evaluation, and Management, 2nd ed. New York: Oxford University Press; 2000.
Cohen M. Craniosynostosis and syndromes with craniosynostosis: incidence, genetics, penetrance, variability, and new syndrome updating. Birth Defects: Original Article Series 1979;15:13–63.
Williams JK, Ellenbogen RG, Gruss JS. State of the art in craniofacial surgery: nonsyndromic craniosynostosis. Cleft Palate Craniofac J 1999;36:471–485.
Panchal J, Uttchin V. Management of craniosynostosis. Plast Reconstr Surg 2003;111:2032–2048.
Persing J, Jane J, Shaffrey M. Virchow and the pathogenesis of craniosynostosis: a translation of his original work. Plast Reconstr Surg 1989;83:738–742.
Moss M. Twenty years of functional cranial analysis. Am J Orthod Dentofacial Orthop 1972;61:479–485.
Aldridge K, Marsh JL, Govier D, et al. Central nervous system phenotypes in craniosynostosis. J Anat 2002;201:31–39.
Passos-Bueno MR, Wilcox WR, Jabs EW, et al. Clinical spectrum of fibroblast growth factor receptor mutations. Hum Mutat 1999;14:115–125.
Perlyn CA, Marsh JL, Pilgram TK, et al. Plasticity of the endocranial base in nonsyndromic craniosynostosis. Plast Reconstr Surg 2001;108:294–301.
Schmelzer R, Perlyn C, Kane A, et al. Patterns of calvarial dysmorphology in sagittal synostosis. Paper presented at the American Cleft Palate–Craniofacial Association Annual Meeting; Minneapolis, MN; 2001.
Marsh JL, Jenny A, Galic M, et al. Surgical management of sagittal synostosis. A quantitative evaluation of two techniques. Neurosurg Clin North Am 1991;2:629–640.
Richtsmeier JT, Cole TM III, Krovitz G, et al. Preoperative morphology and development in sagittal synostosis. J Craniofac Genet Dev Biol 1998;18:64–78.
Zumpano MP, Carson BS, Marsh JL, et al. Three-dimensional morphological analysis of isolated metopic synostosis. Anat Rec 1999;256:177–188.
Kapp-Simon KA. Mental development and learning disorders in children with single suture craniosynostosis. Cleft Palate Craniofac J 1998;35:197–203.
Lo LJ, Marsh JL, Kane AA, et al. Plagiocephaly: differential diagnosis based on endocranial morphology. Plast Reconstr Surg 1996;97:282–291.
Lo LJ, Marsh JL, Kane AA, et al. Orbital dysmorphology in unilateral coronal synostosis. Cleft Palate Craniofac J 1996;33: 190–197.
Kane AA, Lo LJ, Vannier MW, et al. Mandibular dysmorphology in unicoronal synostosis and plagiocephaly without synostosis. Cleft Palate Craniofac J 1996;33:418–423.
Cohen MM Jr. Lambdoid synostosis is an overdiagnosed condition. Am J Med Genet 1996;61:98–99.
Govier D, Kane A, Marsh J, et al. Appearance of sutural patency in lambdoid synostosis is dependent upon plane of CT acquisition. Paper presented at the American Cleft Palate–Craniofacial Association Annual Meeting; Asheville, NC; April 8–12, 2003.
Huang MH, Gruss JS, Clarren SK, et al. The differential diagnosis of posterior plagiocephaly: true lambdoid synostosis versus positional molding. Plast Reconstr Surg 1996;98:765–776.
Huang MH, Mouradian WE, Cohen SR, et al. The differential diagnosis of abnormal head shapes: separating craniosynostosis from positional deformities and normal variants. Cleft Palate Craniofac J 1998;35:204–211.
Mulliken JB, Van der Woude DL, Hansen M, et al. Analysis of posterior plagiocephaly: deformational versus synostotic. Plast Reconstr Surg 1999;103:371–380.
Ehret FW, Whelan MF, Ellenbogen RG, et al. Differential diagnosis of the trapezoid-shaped head. Cleft Palate Craniofac J 2004;41:13–19.
Panchal J, Marsh JL, Park TS, et al. Photographic assessment of head shape following sagittal synostosis surgery. Plast Reconstr Surg 1999;103:1585–1591.
Jimenez DF, Barone CM. Endoscopic craniectomy for early surgical correction of sagittal craniosynostosis. J Neurosurg 1998;88:77–81.
Seymour-Dempsey K, Baumgartner JE, Teichgraeber JF, et al. Molding helmet therapy in the management of sagittal synostosis. J Craniofac Surg 2002;13:631–635.
Gault DT, Renier D, Marchac D, et al. Intracranial pressure and intracranial volume in children with craniosynostosis. Plast Reconstr Surg 1992;90:377–381.
Renier D, Sainte-Rose C, Marchac D, et al. Intracranial pressure in craniostenosis. J Neurosurg 1982;57:370–377.
Kane AA, Kim YO, Eaton A, et al. Quantification of osseous facial dysmorphology in untreated unilateral coronal synostosis. Plast Reconstr Surg 2000;106:251–258.
Becker D, Fundakowski C, Govier D, et al. Long-term osseous morphology of surgically treated unilateral coronal craniosynostosis. Paper presented at the American Cleft Palate– Craniofacial Association Annual Meeting; Chicago, IL; March 16–20, 2004.
Kane AA, Mitchell L, Craven K, et al. Observations on a recent increase in plagiocephaly without synostosis. Pediatrics 1996; 97:877–885.
Marsh JL. Decision Making in Plastic Surgery . St. Louis: BC Decker; 1993.