Craniosynostosis: General

GENESIS

The term craniostenosis (literally translating as “cranial narrowing”) is used to describe the abnormal head shape that results from premature fusion of one or more sutures, whereas craniosynostosis is the process of premature sutural fusion that results in craniostenosis. The term craniosynostosis is used more widely, perhaps in an effort to distinguish deformational nonsynostotic head shapes from those caused by underlying sutural synostosis, but the two terms can be used interchangeably. Plagiocephaly is a nonspecific term used to describe an asymmetric head shape that can result from either craniosynostosis or cranial deformation, and differentiation between these two processes is critical to determining the proper mode of treatment (i.e., surgery versus physical techniques). Synostotic plagiocephaly is usually corrected by a neurosurgical procedure, whereas deformational plagiocephaly responds to early physical therapy, repositioning, and cranial orthotic therapy if these early measures are unsuccessful.

General pediatricians often refer patients for a concern of craniosynostosis when they cannot detect the anterior fontanel or when there is concern for an abnormal head shape with subtle sutural ridging. On average, the anterior fontanel closes at 1 year ± 4 months, the posterior fontanel closes at birth ± 2 months, and the metopic suture by 6 months ± 3 months (10% of adults have an open metopic suture). Clinical closure of sutures is perceived at 6–12 months of age and anatomic closure of sutures by 30th year. In a study of normal infants followed from birth to 24 months, the anterior fontanel was closed in 11% at 3 months of age, 32% at 6 months, 56% at 9 months, 81% at 12 months, 96% at 18 months, and 100% by 24 months ( Fig. 29.1 ).

In an otherwise normal fetus, prenatal limitation of normal growth stretch across a suture during late fetal life can result in craniosynostosis ( Fig. 29.2 ). Craniosynostosis can also occur when the lack of growth stretch is caused by a deficit in brain growth, as in severe primary microcephaly. Experimental prolongation of gestation, which resulted in fetal crowding after installation of a cervical clip in pregnant mice, has been shown to lead to craniosynostosis. The frequency of craniosynostosis was greatest among mouse fetuses located proximally in the uterine horns, where the crowding was most severe. The most common cause of craniosynostosis in an otherwise normal infant is constraint of the fetal head in utero. Factors influencing fetal head constraint can include multiple gestation, macrosomia, oligohydramnios, primigravida, and maternal uterine malformations. When external fetal head constraint limits growth stretch across a cranial sutural area between the constraining points, it may lead to craniosynostosis of an intervening suture (see Fig. 29.2 ). With sagittal craniosynostosis (the most common type), this event usually occurs in an otherwise normal child. The constrained suture tends to develop a bony ridge, especially at the point of maximum constraint between the biparietal eminences. Such ridging can easily be palpated or visualized on skull radiographs, and three-dimensional cranial computed tomography (3D-CT) allows the ridge to be seen even more clearly.

In general, craniosynostosis begins at one point and then spreads along a suture. At the center of the fused suture, there is complete sutural obliteration with nonlamellar bone extending completely across the sutural space, while further away from the initial site of fusion, the sutural margins are closely approximated with ossifying connective tissue. The longer the time before the craniosynostosis is surgically corrected, the greater the tendency for more of the suture to become synostotic, with synostosis beginning at only one location in most cases. Pronounced sutural ridging tends to occur primarily over midline end-to-end sutures (i.e., in sagittal and metopic synostosis). Ridging also occurs with coronal and lambdoidal synostosis, but it may be less prominent than that seen with synostotic midline end-to-end sutures. Synostosis prevents future expansion at that site, and the rapidly growing brain then distorts the calvarium into an aberrant shape, depending on which sutures have become synostotic. The various sutures and fontanels are shown in Fig. 29.3 , and the specific head shapes that result from each type of sutural fusion are shown in Figs. 29.4 and 29.5 . The earlier the synostosis takes place, the greater the effect on skull shape, but the precise mechanisms that lead to sutural synostosis are heterogeneous and incompletely understood. For example, craniosynostosis may result from mutant gene function, storage disorders, hyperthyroidism, or failure of normal brain growth. The topic of craniosynostosis has been comprehensively reviewed by Cohen and MacLean. Molecular characterization of a large cohort of patients evaluated at a single center is summarized by Wilkie et al. Although many patients with a genetically determined cause harbor a variant in one of just seven genes (EFNB1, ERF, FGFR2, FGFR3, SMAD6, TCF12, and TWIST1), over 60 genes are known to be recurrently mutated and often impact the FGF/MAPK, BMP, Wnt, hedgehog, retinoic acid, STAT, and ephrin signaling pathways. Chromosomal aberrations (mostly microdeletions) account for about 6.7–40% of cases of syndromic craniosynostoses and often present with premature fusion of metopic or sagittal sutures plus additional clinical findings.

The frequency of craniosynostosis is 1 per 2000–2500 live births, and it is usually an isolated, sporadic anomaly in an otherwise normal child. Most cases, approximately 73–85%, are isolated and nonsyndromic, while the other 15–27% are recognized as part of an underlying syndrome or are suspected to be syndromic. About 8–15% of all craniosynostosis cases are familial. Familial types of craniosynostosis occur most frequently in coronal synostosis and account for 14.4–22.2% of coronal synostosis, 4–8% of sagittal synostosis, and 5–12.7% of metopic synostosis. Lambdoidal synostosis is almost never familial but has been reported. The frequency of associated twinning is increased and most twin pairs are discordant, especially in sagittal and metopic synostosis; this would tend to support fetal crowding as a cause of these types of synostosis, whereas concordance for coronal synostosis is much higher for monozygotic twins than for dizygotic twins. In 2014, Greenwood et al. reported on 660 mutation-negative nonsyndromic craniosynostosis cases and found that the incidence rate for first-degree relatives of probands was 6.4% for metopic, 4.9% for complex craniosynostosis, 3.8% for sagittal, 3.9% for lambdoid, and 0.7% for coronal cases. Familial craniosynostosis is usually transmitted as an autosomal dominant trait with incomplete penetrance and variable expressivity. A wide variety of chromosomal anomalies have also been associated with craniosynostosis, a fact that emphasizes the importance of karyotype and chromosome microarray analysis for those patients with syndromic craniosynostosis in whom a recognizable monogenic syndrome is not apparent, particularly when there is associated developmental delay and growth deficiency. In addition, craniosynostosis can also occur as a component of numerous syndromes, many of which manifest phenotypic overlap and genetic heterogeneity.

Named syndromes with a demonstrated mutational basis include Apert syndrome, Crouzon syndrome, Pfeiffer syndrome, Saethre-Chotzen syndrome, Jackson-Weiss syndrome, Boston craniosynostosis, Beare-Stevenson cutis gyrata syndrome, and Muenke syndrome. New craniosynostosis-related genes continue to be uncovered as exome sequencing becomes a routine part of evaluation in unrecognized syndromes.

Secondary craniosynostosis can occur with certain primary metabolic disorders (e.g., hyperthyroidism, rickets), storage disorders (e.g., mucopolysaccharidosis), hematologic disorders (e.g., thalassemia, sickle cell anemia, polycythemia vera, congenital hemolytic icterus), brain malformations (e.g., holoprosencephaly, microcephaly, encephalocele, overshunted hydrocephalus), and selected teratogenic exposures (e.g., diphenylhydantoin, retinoic acid, valproic acid, aminopterin, fluconazole, cyclophosphamide, clomiphene citrate). There are recurrent gain-of-function de novo variants in retinoic acid receptor alpha (RARA; c.865 G>A [p.Gly289Arg]) identified in probands with similar phenotypes. Future studies may help decipher potential gene-environment interactions. Recent epidemiologic studies have expanded the knowledge and impact of environmental risk factors in craniosynostosis. Maternal smoking appears to be the greatest risk (odds ratio [OR], 1.6) to the developing fetus after the first trimester, and the risk increases with the number of cigarettes smoked per day. Gestational diabetes is seen at a significantly higher rate in mothers of infants with craniosynostosis than mothers of nonaffected infants. The rates of maternal or gestational diabetes–diagnosed mothers of children with craniosynostosis ranges from 3% to over than 10%. A 2023 study using data from the National Birth Defects Prevention Study demonstrated that mothers who consume high amounts of caffeine (≥300 mg per day) have an elevated adjusted OR (1.3 [95% confidence interval (CI) 1.1–1.6]) of having an infant with craniosynostosis. Rasmussen et al. found that maternal thyroid disease was associated with craniosynostosis after controlling for maternal age with an adjusted OR of 2.47 (95% CI 1.46–4.18).

FEATURES

The impact of craniosynostosis on skull shape is dependent on which sutures are synostotic, the extent of the craniosynostosis, and the timing of the problem. The earlier the fusion, the more profound its impact on subsequent craniofacial development. Craniosynostosis of multiple sutures may limit overall brain growth and result in increased intracranial pressure. Elevated intracranial pressure occurs more commonly with syndromic craniosynostosis and multiple sutural synostosis. On skull radiographs, increased intracranial pressure due to craniosynostosis may be associated with a “beaten copper” appearance. The precise reason for this phenomenon is not known, but it may be the result of the altered magnitude and direction of forces on the bony trabecular organization within the calvarium. A copper-beaten appearance of the skull has poor sensitivity in detecting increased intracranial pressure, as such an appearance can also be seen in normal patients. In children older than 8 years, the finding of papilledema indicates the presence of increased intracranial pressure, but the absence of papilledema in younger children is not predictive of normal pressure. Pronounced sutural ridging occurs primarily in sagittal and metopic synostosis, and these midline, end-to-end sutures may be predisposed toward ridging when they become synostotic. It is important to distinguish craniosynostosis in normal-appearing infants from that which occurs in association with genetic syndromes. Ridging of one lambdoid suture occurs commonly with lambdoid synostosis, and such ridging helps distinguish lambdoidal synostosis from deformational posterior plagiocephaly. Ridging occurs infrequently in unilateral coronal craniosynostosis, suggesting that some of these cases may have a constraint-related phenotype, but unless a mutation is detected, it is virtually impossible to distinguish between coronal synostosis due to fetal head constraint and genetic craniosynostosis.

Inability to demonstrate a mutation does not rule out a genetic basis for the craniosynostosis, and not every person with a mutation manifests craniosynostosis. Bilateral coronal synostosis often lacks sutural ridging and usually has a genetic pathogenesis, which suggests that all such patients should be screened for mutations. Approximately 25–30% of craniosynostosis cases are syndromic, defined by the presence of additional anomalies, developmental delay, intellectual disability, or other major findings. As the costs of genetic testing has decreased, many large academic centers have begun advocating for comprehensive whole-exome/whole-genome testing as a first-tier test to screen for rare or novel genetic causes of syndromic craniosynostosis yet the majority of craniofacial centers continue to rely on a tiered systematic clinical approach starting with a comprehensive examination, gene panel, and microarray before considering broader testing. At a minimum, mutation analysis should be performed in all patients with coronal synostosis.