Clinical manifestations

Presentation and course

Characteristic changes in head shape reflect involvement of specific cranial sutures. Normal skull development initiates around day 23 to 26 of gestation. Craniosynostosis can be associated with over 130 different syndromes; however, most commonly present as a single abnormality (09). Over time, a bewildering number of names have been proposed to describe the anatomical consequences of this involvement.

Table 2 describes the common names and the responsible suture(s); the accompanying figures illustrate head shape (somewhat exaggerated).

Table 2. Craniosynostosis: Anatomical Classification

Because craniofacial bones grow as an integrated unit, most synostoses cause significant change in basicranial and midfacial bones. Metopic and coronal stenoses result in small anterior fossae; coronal stenosis produces shallow orbits; lambdoidal and bilateral coronal stenosis produce forward displacement of the petrous bone. Stenosis of the coronal suture as it continues as the sphenofrontal suture and the sphenoethmoidal suture affect the size of the nasopharynx and apposition of the epiglottis to the soft palate. Isolated sagittal synostosis, the most common, is rarely associated with deformity of the skull base or facial bones.

As the extent of craniosynostosis increases, the number of associated problems also increases. Prominent among these are ophthalmologic disorders, airway obstruction, and feeding difficulties. Refractive error is common in children with craniosynostosis because of alteration in shape of the globe and position of the eyes. In children with syndromic craniosynostosis amblyopia caused by strabismus, ametropia, or ptosis is also seen (47). Decreased central visual acuity and optic atrophy is less common, but may also occur (79).

Psychomotor retardation is uncommon in single suture synostosis (108; 60), although minor delays are frequently found with careful testing (102; 103). Sagittal nonsyndromic craniosynostosis is associated with a high prevalence (> 50%) of deficits in executive function, and research has depicted altered neocortical structural and functional connectivity in these patients (05). However, children with multiple suture closure exhibit developmental delays, particularly those with syndromic craniosynostosis (97). Although many syndromes involve congenital cerebral anomalies, there is evidence of progressive neurologic deterioration in some (27; 36; 58). The most likely explanation of such progressive impairment is cranial growth restriction and resultant increased intracranial pressure. Small crania and elevated intracranial pressure complicate 26% to 54% of multiple suture synostosis but also involve the occasional case of isolated suture closure (92). However, even children with unisutural synostosis may have asymptomatic intracranial hypertension (17). Hydrocephalus is also discovered in 12% or more of syndromic craniosynostosis (35; 40) but is uncommon in isolated suture synostosis (17). Syndromic craniosynostosis and cloverleaf skull may be further complicated by hindbrain herniation ("acquired Chiari malformation"), which may require separate decompressive surgery (16). Whether the herniation is purely the result of intracranial crowding or whether suboccipital bony deformities contribute has not been determined.

Prognosis and complications

Outcome should concentrate on 2 areas, the child's appearance and his or her neurologic development. The craniofacial deformity tends to increase with time and may stigmatize the affected child. Decompressive surgery is effective in limiting deformity (37), especially if done early in life.

Rapid brain growth and the flexible cranium allow the head to assume a more nearly-normal shape. There is wide variation of cosmetic outcomes among the different types of synostoses; this appears to be more a matter of the underlying deformities than surgical technique (28).

A more serious problem in children with multiple suture craniosynostosis is that of neurodevelopmental impairment, especially in those with syndromic forms. Once considered an integral part of various syndromes, impaired cognitive development is often the result of associated cerebral anomalies (97). However, there is evidence for progressive deterioration, both clinically (92) and on electrophysiological monitoring, in many of these children (27). In a national sample of 82 children with syndromic craniosynostosis, Maliepaard and colleagues found that the children had full scale IQs similar to the normative population but were at increased risk for development of intellectual disability, internalizing, and social and attention problems (69). Additionally, children with Apert syndrome had lower full scale IQs and children with Muenke syndrome had more social, attention, and inattention problems. There are often symptoms and signs of intracranial hypertension, which may lead to blindness. This suggests that increased intracranial pressure secondary to restricted brain growth and hydrocephalus (or other factors) may be a contributing factor. Indeed, early and aggressive cranial decompression has allowed relatively normal neurodevelopmental progress, even in some children with syndromes thought to be uniformly associated with mental retardation (95). However, restenosis, hydrocephalus, and even hindbrain herniation may occur despite surgical decompression (116). Treatment of hydrocephalus poses a difficult management issue because it can secondarily contribute to premature suture closure and growth arrest (113). Even children with successful surgery for single suture synostosis can develop craniosynostosis of multiple sutures and increased intracranial pressure; postoperative patients must be carefully followed (52). Early surgery does not assure normal cognitive development; children with early repair of sagittal or metopic synostosis do not score as well as controls at school age (120; 102; 103). However, early surgery improves developmental level (06). Additionally, early surgical reconstruction helps limit progressive deformity of the cranial base. Infants retain malleability in the skull leading to easier shaping (09). Early diagnosis and treatment are essential factors in preventing serious complications and improving long-term outcome (36; 58).

Clinical vignette

The full-term product of a normal pregnancy, labor, and delivery was noted to have a long, narrow head. There was no family history of craniocerebral deformities, and the child was neuroradiologically normal on examination. Skull radiographs and CT scans confirmed isolated synostosis of the sagittal suture. The deformity progressed, and at 6 weeks of age the child was admitted for surgery.

An extensive decompression of the skull was performed, with excision of the stenotic suture and enlargement of adjacent sutures down to the skull base.

Improvement in cranial appearance was rapid and has been maintained despite rapid regrowth of craniectomized bone.

Subsequent appearance and neurologic development are normal.

Biological basis

Etiology and pathogenesis

Primary synostoses may be divided into nonsyndromic and syndromic types. Most cases of nonsyndromic craniosynostosis are isolated and sporadic; however, a small percentage reflect autosomal dominant inheritance. Studies of nonsyndromic, midline synostoses among twins suggest both genetic and environmental components (64). Exome sequencing of 291 parent-offspring trios with midline nonsyndromic synostoses revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling. The findings in this study implicate new genetic involvement in nonsyndromic craniosynostosis and demonstrate a relation in the pathophysiology of nonsyndromic and rare syndromic forms of craniosynostosis (117). Syndromic craniosynostosis, on the other hand, is usually inherited, again with occasional sporadic cases. The syndromes exhibit considerable genetic heterogeneity (82). Inheritance of several syndromes is listed in Table 1. Several chromosomal anomalies, apart from those associated with specific genetic mutations, are also associated with craniosynostosis. Genetic factors include mutations in EFNB1, EFNA4, MSX2, FGFR 1-3, SHOC2, and TWIST1 genes. Proteins encoded by these genes control the intramembranous ossification of the skull (77; 66). Primary craniosynostosis may also be a teratogenic effect of valproic acid, retinoic acid, cancer chemotherapy, or phenytoin (19; 39).

Secondary craniosynostosis results from premature closure of sutures; it occurs occasionally in children with microcephaly and rarely in children who have been shunted for hydrocephalus. Metabolic disorders such as hypophosphatemic rickets and hyperthyroidism may cause craniosynostosis. It is also an occasional finding in the mucopolysaccharidoses and mucolipidoses. Rarely, secondary craniosynostosis may result from marrow hyperplasia and osseous overgrowth in hematologic disorders, such as sickle cell anemia or the thalassemias (18). Amniotic band syndromes are associated with craniosynostosis, along with facial and cranial clefts, limb amputations, and other birth anomalies. Workers at the Centers for Disease Control have reported an association between fertility treatment and craniosynostosis (91).

Our present understanding of cranial morphogenesis is best approached historically. In the 19th century it was universally believed that the skull grew by apposition of new bone at the margins of cranial sutures. Sommering proposed that premature suture closure prevented normal skull growth perpendicular to the involved suture (107). Virchow added to this theory the idea of compensatory growth parallel to the closed suture (119). Some aspects of this hypothesis have been enlarged to explain the evolution of abnormal head shape in craniosynostosis. Normal closure of sutures varies between individuals; however, the metopic suture usually closes within the first 2 years of life. The sagittal, coronal, and lambdoid sutures close by 40 years of age, whereas the squamosal, occipitomastoid, and sphenotemporal sutures may remain partly open at age 70 years (24). However, the basic premise that skull growth occurs only at cranial sutures cannot be correct.

Furthermore, the calvarium consists of membranous bone, sandwiched between the outer dural layer (endocranium) and the pericranium. Calvarial growth occurs by a repetitive cycle of suture widening and ossification of enlarging membranous bones (32).

Moss presented an explanation of normal and abnormal skull growth that relied on biomechanical forces originating from the skull base (76). He proposed that dural bands, originating at the skull base, created growth vectors for the calvarium. Cranial sutures formed along these vectors kept patent by biomechanical forces. Interference with these vectors, usually the result of synchondrosis at the skull base, caused the affected suture to close prematurely. Transfer of force to adjacent growth sites completes the deformity.

However, investigations have cast doubt on the Moss hypothesis. Experimental closure of vault sutures can cause craniostenosis and facial deformities typical of the clinical syndromes (89). This reversal of the direction of influence undermines the idea of the skull base as the origin of changes. Local dura, rather than transmitted forces, seems to be most important in determining sutural patency (12) and the timing of suture closure (67). There is accumulating evidence that biomechanical forces do not play a major role in sutural growth and closure; these processes instead respond to complex cell signaling mechanisms (84; 01). It has long been presumed that restricted head growth is responsible for the associated intracranial hypertension and mental retardation. However, computer analysis of intracranial volumes over time suggests that skull constriction effects of synostosis dissipate over the first few months of life (100; 70; 78; 99). Furthermore, impaired venous drainage may play a larger and more durable role than previously suspected (115; 94; 43). Increased intracranial pressure is thought to result from restricted venous outflow, secondary to the obstruction of the skull base venous structures from alterations in the cranial vault (10; 113). A similar role has been implicated for upper airway obstruction and hydrocephalus (43; 114). The latter is an especially common finding in children with syndrome craniosynostosis, and it poses a significant management issue. CSF diversion, although beneficial for the treatment of hydrocephalus, may contribute to further fusion of the sutures and growth arrest for the cranial vault (43; 113).

Advances in molecular genetics have identified the importance of fibroblast growth factor receptors in the biology of syndromic craniosynostosis (122). Fibroblast growth factor receptors are tyrosine kinases that transduce signals from extracellular fibroblast growth factors into the cell. Mutations of fibroblast growth factor receptor 2 result in a spectrum of craniofacial abnormalities, including the syndromes of Crouzon, Pfeiffer, Apert, and Jackson-Weiss (109; 81; 13; 38). These mutations are associated with an increase in alkaline phosphatase activity and osteocalcin production, which causes localized proliferation of osteoblastic cells and increased bone formation at the suture site (25). The fibroblast growth factor receptor 2 gene is located on chromosome 10q, whereas fibroblast growth factor receptor 1 and fibroblast growth factor receptor 3, both of which have also been associated with autosomal dominant craniosynostosis, are located on chromosomes 8p and 4p, respectively. In children with Apert syndrome, 2 adjacent amino acid substitutions account for the fibroblast growth factor receptor 2 abnormality. In other syndromes, mutations may be characterized by amino acid substitutions, deletions, insertions, or splice-site mutations. Fibroblast growth factor receptor 3 mutation has been implicated in some nonsyndromic cases (93). In addition to these genes for growth factor receptors, craniosynostosis may be associated with mutation of homeobox genes and genes involved in apoptosis (48), a process shown to be important in suture formation and maintenance (11). Identical mutations may produce different phenotypes, suggesting other, as yet undiscovered, genes are also involved (63).

Additionally, mutations in these genes and several others have been implicated in non-syndromic single suture craniosynostosis. In particular, TWIST1 has been associated with the development of single suture craniosynostosis (66). It is a transcriptional regulator of mesenchymal cell fate during skeletal development, inducing differentiation toward both the chondrogenic and the osteogenic lineages. In Drosophila, twist homozygous mutations disrupt embryo gastrulation and result in failure of mesodermal-derived organ development leading to complete eversion of the head. Genome wide screening for copy number variations and intense genomic resequencing allowed the identification of other previously unknown gene variants that can be associated with different single suture craniosynostosis types (73; 23).

Epidemiology

The incidence of craniosynostosis is estimated to be 1 in 2000 children (65), although the incidence of any of more than 100 syndromic craniosynostoses varies widely. It is estimated that Crouzon syndrome occurs once in 25,000 births, whereas Apert syndrome occurs once in 100,000 births. A craniosynostosis registry maintained for 3 years in Colorado revealed a birth prevalence of 14.1 per 10,000 live births (02).

The sagittal suture is the most commonly involved suture, constituting more than half of all craniosynostosis. Sagittal synostosis is rarely syndromic, and is more frequent in males by a ratio of 3:1 (53). Unilateral or bilateral involvement of the coronal suture is the next most common; however, the male:female ratio is 1:2 (65). Bilateral coronal synostosis is more frequently familial than unilateral synostosis, and it is often associated with involvement of other sutures. Metopic synostosis occurs in less than 10% of nonsyndromic craniosynostosis. However, most series represent patients with clinically significant craniosynostosis. Lesser degrees of metopic stenosis may exhibit a palpable ridge and slight hypotelorism; this is probably the commonest craniosynostosis (104). Examination of portraits and the exhumed skull of the composer Wolfgang Amadeus Mozart confirms he had metopic synostosis (90). Progression of isolated, single suture synostosis to that of multiple sutures is uncommon.

Prevention

There appears to be an increased risk of craniosynostosis in the offspring of mothers who smoke or live at high altitude (03) and who take certain medications during pregnancy (19). Fetal ultrasound studies have identified syndromic (61; 106) and isolated (111) sutural synostosis early in pregnancy. Apert syndrome has been confirmed by molecular diagnosis of amniotic fluid (33). There is laboratory evidence that opening involved sutures in utero can minimize craniocerebral changes (112).

Differential diagnosis

In the neonate, craniosynostosis must be differentiated from modeling of the calvarium, which may be caused by abnormal intrauterine positioning or vaginal delivery. Premature infants may have dolichocephaly without sagittal synostosis (50). Many cultures practice infant head wrapping and molding, another source of confusion (34). Asymmetric skull growth may be found in children with chronic subdural hematomas, slowly growing brain tumors, and cerebral hemiatrophy (32).

Multiple secondary suture synostosis may occur in disorders with decreased brain volume or microcephaly. These include fetal alcohol syndrome, prenatal infection, hypoxic-ischemic encephalopathy, Chiari malformation, shunted hydrocephalus, and a variety of underlying genetic or metabolic disorders. Appropriate diagnosis of microcephaly may avert unnecessary surgery for secondary craniosynostosis.

The most difficult distinction is in the infant with occipital plagiocephaly. This condition, attributed to unilateral lambdoidal synostosis, was uncommon before the 1990s. A large increase was attributed by Kane and colleagues to the increase in the supine positioning of infants for sleeping (59). In 1992 the American Academy of Pediatrics recommended the “back to sleep” position to prevent sudden infant death syndrome (SIDS). Intrauterine cranial restriction may also play a role (68), and these children usually exhibit some cranial flattening at birth (83). Certainly, there appear clinically to be 2 syndromes: (1) the rare, true lambdoidal synostosis and (2) the much more common lambdoid positional molding (15). Positional plagiocephaly occurs in the absence of suture synostosis and is due to external forces that deform the shape of the skull (ie, when the child is supine) (105). In this condition there is flattening of 1 side of the occiput, with anterior displacement of the ipsilateral ear. Repositioning of the child to the nonaffected side is effective for mild cases. In more severe deformities, helmet therapy is employed with good results for children up to 18 months of age (22).

Diagnostic workup

Because craniosynostosis often starts in utero, the condition should be diagnosable at or shortly after birth. Careful examination of head shape and facial appearance is essential to identify both syndromic and nonsyndromic craniosynostoses, as is limb and general examination for the former. Examination of parents and review of their childhood photographs is important. Anthropometric measurements of the affected child's skull are typically abnormal. In addition to measuring the occipitofrontal circumference, it is helpful to measure the cephalic index, which is the ratio of biparietal diameter to anteroposterior diameter x 100. The normal cephalic index ranges from 78 to 84; scaphocephaly is associated with a decreased value and brachycephaly with an increased value.

A diagnosis of craniosynostosis is usually made by clinical examination; findings include a head shape consistent with the palpably-closed suture(s), often characteristic orbital, maxillary, and limb changes. A palpable ridge may replace the stenosed suture.

Radiologic evaluation offers confirmation and provides supplemental information that may be useful for management. Classic findings on routine x-ray include sclerosis or indistinctness along the suture and ridging of bone at the suture. Skull radiographs, however, may show synostosis along a few millimeters of suture, despite clinical evidence of inadequate skull growth along the length of the suture. CT scanning has been considered the best modality for diagnosing craniosynostosis, although problems with volume averaging occasionally interfere with demonstration of small areas of synostosis.

Thin-section, 3-dimensional CT enhances specificity of diagnosis and provides additional information about associated abnormalities of the basicranial and facial bones (07; 72; 77). Neuroimaging also permits evaluation of the brain, which may be abnormal in children with syndromic synostoses. Like bicoronal synostosis, metopic synostosis is associated with other abnormalities, such as cleft palate and holoprosencephaly. MRI offers additional information about neuronal migration abnormalities, hindbrain herniation and brainstem compression, delayed myelination, and oropharyngeal obstruction (45). Rozovsky and associates showed that cranial ultrasound is useful as a first-line imaging examination for diagnosis of craniosynostosis as it provided substantial accuracy for detection with 100% sensitivity and 98% specificity (96). Additionally, the use of cranial ultrasound removes the harmful effects of ionizing radiation which can be particularly deleterious in young infants (96). Also, it can be diagnosed intrauterine by a variety of neuroimaging techniques that can improve outcome in these children (46). Neuroimaging may not be essential unless there is some question regarding the diagnosis or where help is needed in surgical planning (14).

Secondary radiologic signs of craniosynostosis are caused by the deforming pressure of growing brain after suture closure. Elevated intracranial pressure in children with multiple suture stenosis may lead to increased convolutional markings, erosion of the floor of the sella turcica, and flattening of the anterior and posterior clinoids.

Cervical spine radiographs should be considered to identify craniovertebral abnormalities or instability that may lead to spinal cord injury during prone positioning for surgery.

Neuropsychological testing should be obtained to provide a useful baseline and serial monitor of developmental progress in children with craniosynostosis. With younger children, in whom such testing is difficult and not always reliable, serial evoked responses can be used to monitor neurologic development (27).

Management

Treatment approaches depend on the type of craniosynostosis and the age of the child. Knowledge of the child's developmental potential and parental expectations may also guide selection of management options. There is no clear-cut evidence that positional or deformational occipital plagiocephaly requires surgical correction or orthotic devices. There is also less enthusiasm for operation in milder forms of metopic synostosis, as untreated cases may not progress.

Surgery for craniosynostosis is guided largely by the sutures involved and the patient’s age and appearance.

Simple linear craniectomy rarely produces satisfactory results; more complex procedures are typically required for removal of abnormal sutures and reconstruction of the skull. Blood loss and transfusion needs can be minimized by technical adaptations (110). Some surgeons recommend a staged craniectomy, whereas others recommend a morcellation procedure or "expanding cranioplasty," allowing immediate, partial reshaping of the calvarium (75; 51). This procedure involves separating the calvarium into several segments of bone that can be repositioned, thereby allowing future growth and remodeling. Hashim and colleagues compared neuropsychological outcomes following treatment with whole-vault cranioplasty or endoscopic strip craniectomy for patients with sagittal craniosynostosis and reported that patients undergoing early whole-vault cranioplasty attained higher intelligence quotient and achievement scores relative to those undergoing strip craniectomy (42).

Timing of surgical intervention is important, as it affects the capability of the craniofacial bones to achieve a more nearly normal pattern of growth (86; 88; 101). Because the rate of brain growth decreases in older children, those with craniosynostosis may require more extensive surgery to achieve results similar to those achieved in younger children with limited surgery. Sagittal synostosis is best treated as early as 6 weeks of age. Surgery by 3 to 6 months of age permits restoration of near-normal skull contour. Surgery for children under 1 year of age requires loose fixation of bone segments to allow for brain growth, whereas those over 3 years of age require rigid fixation (87). Because metallic hardware often erodes through thin scalps, absorbable cranial fixation devices have been developed (29). Although early surgery is optimal for most calvarial abnormalities associated with craniosynostosis, surgical treatment of associated facial abnormalities should be delayed. Premature treatment of midface hypoplasia impairs growth potential and ultimately causes greater facial deformity. Changes of the cranial base that accompany synostosis of individual cranial sutures develop slowly. Based on their studies of orbital development, Bentley and colleagues recommend that frontoorbital advancement surgery be delayed until late in the first year of life (08). Distraction methods have high success rates in older children (80). Illustrations of surgical technique and results include skin incision, sagittal synostosis, and synostoses.

A minimally invasive surgical approach has surfaced with the introduction and widespread use of endoscopic suturectomy (74). This is based on the principle that if timely intervention occurs, the rapidly growing brain will cause expansion of the skull into the normal shape. The procedure involves the insertion of the endoscope through small scalp incisions and the subsequent removal of a strip of bone including the fused suture (74). No internal fixation is used. It is generally recommended for younger children and involves the use of a postoperative cranial molding helmet. Surgeons have been able to demonstrate minimal blood loss, short operative times, early hospital discharge, and excellent functional and cosmetic results for these procedures (55; 49). The efficacy of this technique has been established in the treatment of isolated sagittal synostosis (55). Several groups have expanded the use of the endoscope for other forms of single suture synostosis (56; 57; 41). Additionally, cost analysis has shown that endoscope-assisted craniectomy plus helmet therapy is a less costly surgical option for patients with sagittal craniosynostosis than open cranial vault repair (121).

Children with extensive craniosynostosis require a multidisciplinary approach involving ophthalmologists, geneticists, psychologists, orthodontists, and pediatricians, in addition to neurosurgeons, maxillofacial surgeons, and plastic surgeons. Comprehensive ophthalmologic evaluation is essential. Corrected visual acuity is the best measure of central afferent function. Examination of the fundi and visual fields permit assessment of possible increased intracranial pressure. Examination should include cycloplegic refraction and investigation of individual and conjugate eye movements. Because of shallow orbits in many children with craniosynostosis (30), the risk of exposure keratopathy should also be determined. Associated hydrocephalus rarely responds to synostosis surgery and must be shunted (21).

Genetic counseling is important, particularly in view of mosaicism and variability of penetrance and expression in dominantly inherited syndromic craniosynostoses. Problems with hearing, feeding, and failure to thrive require the oversight of a pediatrician. Developmental problems may require consultation with a neuropsychologist. Family counseling is especially important (98).

Special considerations

Pregnancy

There is a higher incidence of perinatal complications associated with prenatal craniosynostosis (46).

Anesthesia

Increased intracranial pressure, airway impairment, and associated anomalies present special anesthetic risks in these children, requiring careful planning (118; 71). Perioperative airway management is required in a large proportion of children with craniofacial anomalies (85; 71).