Cranial sutures: a multidisciplinary review

Childs Nerv Syst (2013) 29:893–905 DOI 10.1007/s00381-013-2061-4

REVIEW PAPER

Cranial sutures: a multidisciplinary review Antonio Di Ieva & Emiliano Bruner & Jennilee Davidson & Patrizia Pisano & Thomas Haider & Scellig S. Stone & Michael D. Cusimano & Manfred Tschabitscher & Fabio Grizzi

Received: 6 February 2013 / Accepted: 21 February 2013 / Published online: 8 March 2013 # Springer-Verlag Berlin Heidelberg 2013

Abstract Introduction Progress in cranial suture research is shaping our current understanding of the topic; however, emphasis has been placed on individual contributing components rather than the cranial sutural system as a whole. Improving our holistic view helps further guide clinicians who treat cranial sutural abnormalities as well as researchers who study them. Materials and methods Information from anatomy, anthropology, surgery, and computed modeling was integrated to provide a perspective to interpret suture formation and variability within the cranial functional and structural system. Antonio Di Ieva and Emiliano Bruner contributed equally to the work. A. Di Ieva (*) : J. Davidson : S. S. Stone : M. D. Cusimano Division of Neurosurgery, St. Michael’s Hospital, 30 Bond Street, M5B 1W8, Toronto, ON, Canada e-mail: [email protected] A. Di Ieva e-mail: [email protected] A. Di Ieva : T. Haider : M. Tschabitscher Centre for Anatomy and Cell Biology, Department of Systematic Anatomy, Medical University of Vienna, Vienna, Austria E. Bruner Centro Nacional de Investigación sobre la Evolución Humana, Burgos, Spain P. Pisano Department of Neurosurgery, IRCCS Policlinico S. Matteo, Pavia, Italy

Results Evidence from experimental settings, simulations, and evolution suggest a multifactorial morphogenetic process associated with functions and morphology of the sutures. Despite molecular influences, the biomechanical cranial environment has a main role in both the ontogenetic and phylogenetic suture dynamics. Conclusions Furthering our holistic understanding of the intricate cranial sutural system promises to expand our knowledge and enhance our ability to treat associated anomalies. Keywords Braincase . Cranial anatomy . Craniosynostosis . Fractal geometry . Functional craniology . Sutures

Introduction Cranial sutures have a relevant role both in the evolutionary and biomedical context. Taking into consideration the importance of sutures in shaping cranial morphology in normal and pathological variations, this paper provides a general overview of this issue by integrating information from different disciplines. Topics discussed include historical findings, anatomy, embryology and development, clinical and surgical importance, anthropology, craniology, and morphometrics of cranial sutures. A multidisciplinary approach is necessary to understand the complex mechanisms behind the suture dynamics and to promote basic research as well as surgical treatments associated with their functional and structural defects.

Historical overview M. Tschabitscher Department of Anatomy, University of Brescia, Brescia, Italy F. Grizzi Humanitas Clinical and Research Center, Rozzano, Milan, Italy

Hippocrates (∼460–370 BC) had already mentioned cranial sutures in his notations by describing different types of cranial suture morphologies and advising readers against

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applying trephination over a suture due to the risk of harming underlying dura [1, 2]. Later, Galen (∼129–200 AD) delivered only a superficial description of the cranial commissures in his work “De iuvamentis membrorum”. It took several more years until more distinct descriptions were recorded. Avicenna (980–1037 AD) described clearly the different sutures of the cranium in his “Canon”. He was probably the first to describe the coronal suture, picturing it as “an arc in whose center a perpendicular line has been set up” [3]. Furthermore, he characterized the sagittal suture as the suture that divides the skull into two halves. He also explained the name of the lambda suture with its form being similar to the Greek letter lambda (Λ). The famous surgeon William of Saliceto (1210– 1277 AD) used himself this terminology. Furthermore, he named the bones after their related suture (for example referring to the frontal bone as Os coronale) [4]. A famous student of William of Saliceto was Lanfranc of Milan (∼ 1250– 1306 AD) who carried his teacher’s ideas to France, writing clear descriptions of the cranial sutures in his work. Henri de Mondeville, teacher of Guy de Chauliac, proposed to use the cranial commissures as landmarks for skull serration in dissection demonstrations. In his work, after studying thousands of skulls in Paris, he negated differences of the cranial sutures between men and women, which was claimed by Aristotle and widely accepted by anatomists at that time [4]. A clear depiction of the sagittal and coronal sutures can be seen in the Plate XI of the Guido da Vigevano’s “Anathomia Designata per Figures”, the first illustrated textbook of modern anatomy, written in 1345 [5] (Fig. 1). Besides contributing knowledge of proper head injury treatment, Berengario da Carpi (1460–1530), a surgeon

and anatomist of the Renaissance, made the important finding in skull anatomy that adhesion of dura underlying cranial sutures is not stronger in comparison to other regions, which was commonly believed by physicians at that time [6] (Fig. 1). With his “Anatomia capitis humani”, published 1536 in Marburg, Johannes Dryander had the ambitious goal to completely cover human head anatomy in 12 figures. In one of his descriptions, he claimed that the frontal suture persists more often in females than in males [7] (Fig. 1). In his famous book “De humani corporis fabrica,” Andreas Vesalius (1514–1564 AD) described in detail the different skull and suture morphologies. He was able to associate cranial morphology with certain pathologies [8]. The first to identify the real cause of craniosynostosis was Rudolph Virchow (1821–1902) [8].

Fig. 1 On the left: Drawing of a dissection of a human head by Dryander of Marburg (1500–1560) with detailed coronal and sagittal suture. In the center: Drawing of Guido da Vigevano (1280–1349) showing a removed cranial vault, on which the frontoparietal and

interparietal sutures can be recognized. On the right: Berengario da Carpi’s (1460–1530) drawing of a human skeleton with distinct representation of the cranial sutures

Anatomy and embryology of the cranial sutures Cranial sutures are synarthroses, meaning forms of articulation in which the bones are rigidly joined by fibrous tissue. In adult humans, the cranial vault comprises 15 sutures: three single sutures (i.e., coronal, sagittal, and lambdoid), and several paired sutures (i.e., squamous, spheno-frontal, spheno-squamous, spheno-parietal, parieto-mastoid, and occipito-mastoid). Suture morphogenesis has been studied by in vitro and in vivo means as a “cranial suture complex”. The cranial suture complex is composed of the underlying dura mater, the osteogenic fronts of the calvarial bone plates, the intervening cranial suture mesenchyme, and the overlying pericranium [9]. A number of animal model systems, such as the mouse, rat, and

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rabbit, have been studied extensively. Although numerous studies have attempted to define the individual contributions of these components, a holistic view remains to be elucidated. Cranial sutures are initially flexible joints between the developing calvarial bones, formed by bands of fibrous connective tissue that prevent premature bone separation [10], allowing the skull to change shape accommodating for growth. The skull of the human embryo begins developing between 23 and 26 days of gestation and is composed of mesoderm and ectomesenchyme, which is derived from the cranial neural crest (CNC) [11, 12]. The dura mater appears between 51 and 53 days of gestation [11]. Cells in the middle of sutural tissue remain undifferentiated whereas cells near the edge of the growing osteogenic front become part of the membranous bone [9, 13]. The embryologic origin of the skull vault has been demonstrated by using Wnt1-Cre/R26R construct mice to distinguish between neural crest-derived and mesodermal components of cranial skeletogenic mesenchyme [14–16]. The neurocranium develops from the surrounding mesenchyme while the viscerocranium (the facial skeleton) is derived from the first three branchial arches [11]. Within the neurocranium, there are further subdivisions: the cranial base; the chondrocranium, which refers to the cranial base bones that originate from the paraxial mesoderm and undergo endochondral ossification; and the cranial vault [17]. All calvarial sutures are initiated at a juxtaposition line between neural crest and mesoderm, excluding the metopic suture, which is entirely within the neural crest [18]. As suggested by Morris-Kay et al. [18], this may have relevance in explaining the early fusion of this suture in the human skull. Sutures grow perpendicularly to their orientation, and this process is normally maintained throughout the period of growth of the brain [18]. Appositional growth involves osteoclastinduced bone breakdown on the inner surface of the skull and osteoblast-mediated thickening on the outer surface [18]. Until recent years, it was believed that the dura only served a mechanosensory purpose, namely to transduce the signals controlling skull growth in response to mechanical stress from the expanding brain. In fact, it was later demonstrated that the dura mater secretes large amounts of soluble factors, including peptide growth factors and chemokines for the morphogenesis of the calvaria [19, 20], where sutures develop at the sites of dural reflections [11]. Thus, the early form and growth of the brain is the major determinant of both the presence and position of cranial sutures [21]. In contrast to calvarial sutures, facial sutures do not have underlying dura yet appear morphologically alike, probably due to regulation by surrounding tissue in a similar way to the dura [22]. Many studies note that the dura is highly osteogenic, showing its capacity to completely re-ossify the cranial vault after craniectomy in mice [23–25]. Bradley and colleagues confirmed this observation by culturing posterior interfrontal sutures of

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mice both in the presence and absence of their underlying dura mater. In the presence of dura mater, these sutures fused, comparable to that seen in vivo. However, they remained patent in culture indefinitely in the absence of dura mater [26]. In accordance with these findings [26], Opperman et al. transplanted the coronal suture complex, both with and without dura mater, from embryonic day-19 and postnatal day-1 rats into adult rats with parietal defects. After 3 weeks, transplantations without the dura mater fused abnormally compared to those in the presence of dura mater [27]. They also found that removal of the periosteum did not lead to suture obliteration [28]. This suggests that the overlying periosteum may not be as essential as the dura mater for the development and maintenance of patency of cranial sutures [9]. Levine et al. additionally demonstrated that the dura shows regional differences in its ability to determine fusion or regulate suture patency in the rat model. A 180° calvarial rotation of a craniectomy strip was applied to the experimental group, inclusive of the posterior-frontal and sagittal sutures, placing the posterior-frontal suture into the sagittal suture’s anatomic position and vice versa [29]. The authors found the posteriorfrontal anatomic suture (actual sagittal suture) fused between 20 and 40 days, whereas the suture in the sagittal anatomic position (actual posterior-frontal suture) remained patent throughout the study [29], indicating that the dura underlying the suture in the sagittal anatomic position became imprinted with a signal preventing osteogenic fusion. These results clearly depicted the system’s necessity in preventing fusion driven by the osteogenic dura [29]. Regulation of the osteogenic fronts at the sutural interface is maintained via a delicate balance between cell proliferation, differentiation, migration [11], and apoptosis [30], which ensures a steady equilibrium of growth and separation [30–36]. The roles of fibroblast growth factor receptors (FGFR-1, -2, -3, -4) [37], transforming growth factors of the beta super-family (TGF-β1, -2, -3) [38], and Ephrin-eph signaling are documented in suture morphogenesis. FGFRs are effective by activating a tyrosine kinase pathway [11]. Ephrins are membrane-bound ligands that interact with Eph receptors, a family of receptor tyrosine kinases [34, 39–41]. Current studies on cranial sutures support a role for FGFR-1 in promoting osteoblast differentiation; FGFR-2 in proliferation, although absent from the suture and dura; FGFR-3 as an inhibitor of proliferation during chondrogenesis, found mostly in cartilaginous tissue; and FGFR-4 as it is highly expressed in brain tissue but not in craniofacial sutures [17]. TGFs-1, -2, and -3 purportedly have an important role in calvarial bone growth and patency and have been found in the bone fronts and dura but not the sutural mesenchyme [17]. TGFs-1 and -2 play a role in obliterating sutures, while TGF-3 is expressed in non-fusing sutures [17]. A common method of uncovering which genes, molecules, and cellular mechanisms are responsible for sutural

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development is to investigate mutations associated with sutural anomalies, such as in craniosynostosis syndromes. Along these lines, studies have examined animal models harboring mutations in the homeobox gene, Msx2 [42], Ephrin-eph signaling, and FGFRs. For example, syndromic FGFR mutations lead to constitutively active receptors that accelerate suture closure resulting in premature fusion. Kim et al. [43] proposed that signals from the dura mater might regulate the maintenance of sutural patency in the prenatal stage, whereas signals in the osteogenic fronts dominate after birth. Gene expression levels in mice in the sagittal suture during embryonic (E15-E18) and postnatal stages (P1–P6) were measured with in situ hybridization and in vitro analysis [43]: Msx1, Msx2, and Bmp4 were expressed in the sutural mesenchyme and dura mater; FGFR2, Bmp2, and Bmp4 were expressed in the osteogenic fronts; and as expression of Shh and Ptc began, that of Bmp4, Msx2 and Bmp2 decreased along the osteogenic fronts at the end of embryonic development [43]. In both mice and humans, the coronal synostosis phenotype is characterized by a defect in the neural crestmesoderm boundary [34, 44]. This is caused by heterozygous loss of Twist1 function, while non-syndromic coronal synostosis is caused by mutations in the EFNA4 in humans, suggesting EphA4 is a Twist1 effector in coronal suture development [34]. Additionally, DiI labeling of migratory osteogenic precursor cells of the frontal and parietal bones

depicts how Twist1 and EphA4 are required for the exclusion of such cells from the coronal suture [34]. Overall, multiple genes in several signaling pathways govern growth at sutural interfaces, as summarized in Table 1.

Clinical and surgical importance The term “craniosynostosis” refers to the premature fusion of one or more cranial vault sutures and is associated with skull deformities. The overall incidence is 6 per 10,000 live births. Patterns of skull deformities for each suture (metopic, coronal, sagittal, and lambdoid) are characteristic amongst patients, although variable in their degree of severity. They can also be associated with facial deformities, endocranial base abnormalities, various forebrain anomalies, ocular pathologies, cognitive and behavioral impairments, and can induce pathologic increases in intracranial pressure. Craniosynostosis can be non-syndromic (isolated) when it occurs sporadically, or syndromic when associated with an underlying genetic cause for skeletal mal-development. Alterations in the gene family coding for FGFRs have been identified as the genetic cause for most craniofacial syndromes such as Crouzon’s, Apert’s, and Pfeiffer’s syndromes. The care of these patients may be complex and require a multidisciplinary collaboration, including geneticists, neurosurgeons, plastic surgeons, ophthalmologists, otolaryngologists,

Table 1 Summary of the genes involved in the sutures development Gene Humans FGFRs 1-3 MSX2 TWIST1 FIBRILLIN-1 (FBN1) TGFBR1, TGFBR2 EPHRINA4 (EFNA4) EFNB1 RAB23 JAGGED1 (JAG1) Mice

EphA4 Axin2 Msx2

Dusp6 Gdf6 Pdgfr alpha Nell1 Shh Ptc

Supposed function

Reference

Promotes osteoblast differentiation; proliferation; inhibitor of proliferation during chondrogenesis. [17, 37] Craniofacial development. [42] May function as an upstream regulator of FGFRs. [107] Making large protein (fibrillin-1) contributing to microfibrils. [108] Role in obliterating sutures. [17, 38] Boundary formation and pathogenesis of coronal synostosis. Tissue boundary formation. Negative regulator in hedgehog signaling in cranial suture biogenesis. Notch ligand. Specification of sutural cells and mechanisms that maintain a boundary between the osteogenic and non-osteogenic compartments of the coronal suture. Twist1 effector in coronal suture development. Osetoblast proliferation and differentiation, resembling craniosynostosis. Early stages: Transition from undifferentiated, neural crest-derived mesenchyme to early-stage osteoblasts. Appositional growth: Maintains osteoblasts in a proliferative state. Negative feedback regulator of FGFR signaling. Skeletal dwarfism, coronal craniosynostosis. Establishing boundaries between skeletal elements, i.e- coronal suture. Stimulates osteogenesis of NCC-derived osteoblasts. May modulate osteoblast differentiation. Regulating cranial suture development and intramembranous bone formation. Shh receptor.

[44] [109] [110] [111, 112] [34] [113] [114–117]

[118] [119] [120] [121] [43] [122]

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orthodontists, speech and physical therapists, and psychologists. Indications for treatment of craniosynostoses are generally not well established; however, surgical correction is frequently entertained for cosmetic reasons, to reduce the functional consequences associated with raised intracranial pressure, or to decrease breathing, feeding and vision problems. Several techniques of correction are employed, ranging from suturotomy [45, 46], to partial or total craniectomy [47–49], to extensive cranial vault reshaping and reconstruction [50–53], and to more recently emerging minimally invasive endoscopic [54–59] and distraction techniques. Advances in implants, such as absorbable skull mini-plating systems; surgical planning adjuncts, such as pre-operative 3D template modeling; and perioperative care, such as blood transfusion protocols and modern anaesthesia techniques, have improved surgeons’ abilities to perform safe and effective corrections for many of these patients. Despite decades of technical advances and improvements, results are, however, frequently not satisfactory due in part to a high incidence of premature and irregular reossification. In many cases, one or more additional procedures are required as the child continues to grow and mature. Moreover, current treatments impart not insignificant risks of morbidity and even rarely mortality. Indeed, there is a strong clinical impetus to further our understanding of basic mechanisms underlying cranial suture growth and development in order to develop more successful and less invasive means of managing these challenging conditions.

Anthropology and functional craniology Since its beginning in the 18th century, biological anthropology has been deeply rooted in craniological studies; consequently,

Fig. 2 Areas of interest for suture biology in anthropology and general fields of application, shown on the Neanderthal skull Guattari 1, dated around 50,000 years before present (original photograph courtesy of L. Bondioli)

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sutures have been investigated since the early development of this discipline in fields like primatology, paleontology, or archaeology (Fig. 2). Despite this longstanding relationship, little advances were made in sutures biology. Their large degree of variation and fuzzy geometrical organization hampered a proper interpretation of the differences observed between individuals, populations, and species. Many features of sutures are used in population biology as well as in forensic anthropology to evaluate the genetic history of individuals. Persistence or obliteration of sutures has been widely used in bioarchaeology to assess levels of interbreeding or consanguinity between individuals [60, 61]. Such heritability has also been described for non-human primates [62]. In physical anthropology, sutures have also long been used for estimating the age at death of cranial remains, supposing a progressive and shared pattern of their closure along the lifetime [63–66]. Suture closure is supposed to be largely influenced by genetic processes and is hence less sensitive to environmental factors when compared with other kinds of cranial traits used to establish age at death, like dental wear. However, the large inter-individual variation in the timing and scheme of suture closure makes these traits useful only in terms of very large age-classes. Until 40 years of age, sutures follow a more linear pattern of closure, but after 40, there is considerable variation with some individuals undergoing rapid closure and others not exhibiting suture obliteration at all. In terms of evolutionary anthropology, suture anatomy and variation should be compared among primates to provide a proper phylogenetic perspective. Despite most of the cranial sutures being homologous among primate species, differences in the sequence of cranial growth and development are associated with differences in the timing and rate of suture formation and obliteration. For example, most primates retain the premaxillary suture between the maxillary and premaxillary bones (supporting the superior incisive area), while in humans, this suture disappears very early during cranial morphogenesis. This difference is probably related to the greater importance of the growth field associated with the muzzle in non-human primates [67, 68]. In contrast, in those primates developing bone crests and ridges associated with the muscular system (mostly nuchal and temporal muscles), large sutures like the sagittal and lambdoid ones are often covered by bone, particularly in males, after osteoblastic response to muscle tension. Because of the different cranial architecture among primates, suture patterns also vary. An example can be seen at the temporal fossa, which represents a major point of flexion between face and braincase. The meeting point of the four bones involved in this junction is called the pterion. The bones involved are frontal, parietal, sphenoidal, and zygomatic, although even the temporal bone can be part of the pteric areas in some taxa. Old-World monkeys (Catarrhines, including humans) show more frequent contact between the frontal and sphenoid bone, while New World monkeys (Platyrrhines) exhibit more frequent contact between the zygomatic and

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parietal bones [69, 70]. There are, however, many exceptions and their roles in general cranial arrangements remain largely uninvestigated. Among Platyrrhines, for example, howler monkeys (genus Alouatta) show a very peculiar cranial architecture characterized by a marked flexion of the facial axis onto the neurocranial axis [71]. At the same time, they show an arrangement at the pterion, which is similar to that of Catarrhines, suggesting that this suture has probably a relevant structural component. Indeed, variations in primate pterional configuration probably reflect biomechanical influences during morphogenesis since this area represents the hinge between the facial and neurocranial blocks. In anthropology, sutures (and features associated with these elements) are considered “epigenetic traits” or discrete characters, which are the expression of underlying structural patterns [61]. Their sensitivity to the cranial functional matrix has been recognized since the early craniological studies in human paleontology. Actually, because of their role in cranial growth and development, sutures must be interpreted in a structural context. The most relevant advance in suture biology has been the development of a field called “functional craniology” [72] and its application to the study of cranial integration and human evolution [73]. Considering growth as size change and development as shape change during morphogenesis, sutures have both passive and active roles. Throughout ontogeny, sutures coordinate the size variations associated with brain pressure and the shape variations associated with force redistribution by means of connective tensors of the endocranium (falx cerebri, tentorium cerebelli). In addition to these biomechanical factors (Fig. 3) [74]), genetic components [75] also probably contribute through polygenetic cranial factors and pleiothropic effects influencing the cranial architecture. Pathological deformations associated with

craniosynostosis or head shape changes due to cultural practices involve changes in the sutural patterns, possibly by redistribution of tensile forces which may even induce fragmentation of the sutures and formation of additional bone centers [76–78]. Such independent areas of bone formation are called Wormian bones or supernumerary ossicles (Fig. 4). Supernumerary ossicles along the sagittal, coronal, and lambdoid sutures are interpreted as “hypostotic traits”. In other words, characters associated with insufficient ossification. Suture adjustment cannot keep pace with the morphogenesis of adjacent bones or the underlying neural mass because of a lack of equilibrium between growth (size changes) and development (shape changes) of the braincase. On the other hand, an excess of ossification involves an overdeposition of bone tissue, leading to “hyperostotic traits”, like bony superstructures and ridges [79]. According to this perspective, the relationship between suture morphology and genetics may be indirect in the sense that the cranial architecture results from direct genetic determinants, and the sutures then reflect the structural consequences of that architecture. Suture morphology can thus be thought of as heritable to the extent that it reflects heritable aspects of the cranial general organization. Wormian bones, as additional centers of ossification, should not be confounded with multiple bones caused by lack of fusion of sutures. This is the case of the “Inca bones”, which is the result of the persistence of the sutures associated with the multiple centers of ossification of the occipital bone [60]. Even in this case, genetic and biomechanical factors are assumed to be integrated together in generating the final phenotype. It is worth noting that in cases of genetically based additional bones associated with unfused sutures or even with the generation of new cranial elements, the braincase

Fig. 3 The patterns of convolution of the sutures are influenced by biomechanical factors, at both global and local levels. The complexity of the sagittal suture is even influenced by the presence of

the parietal foramina (dots), redistributing the tensile strains and limiting the complexity of the interposed segment of the suture (drawings after [74] courtesy of C.P. Zollikofer)

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Fig. 4 Sutures can be “real sutures”, namely juxtapositions of ossification centers (like in the lambdoid suture; LS), or “false sutures”, in which one element is superposed onto the other (like in the temporal suture; TS). Wormian bones (black arrows) are additional supernumerary ossicles,

interpreted as “hypostotic traits” revealing defects in the ossification process during morphogenesis. In general, these are non-pathological or sub-pathological traits. (Skulls from the Centre for Anatomy and Cell Biology of the Medical University of Vienna, Austria)

geometry may not be affected at all, suggesting the primary role of the brain in shaping the vault morphology and the consequent (and efficient) adjustment of the suture patterns (Fig. 5). This may be the structural context leading to differences between species as well as individuals. Sexual dimorphism for example is largely based on the expression of hypostotic vs. hyperostotic traits. Accordingly, these topics are integral to understanding the variation of these characters within and between groups. Apart from forensic anthropology, bioarchaeology, and population biology, such patterns are also relevant to interpret cranial evolution according to the fossil record, providing

paleoanthropological inferences. For example, Neanderthals simultaneously exhibit flat parietal areas and frequent lambdoid Wormian bones (Fig. 6), suggesting structural constraints possibly associated with the large cranial capacity and unbalance of the growth vs. development morphogenetic patterns [80]. Giuseppe Sergi first proposed that the high frequency of lambdoid ossicles in Neanderthals might be the consequence of a certain morphogenetic instability in the vault organization [81, 82], and Giorgio Manzi used the term “ontogenetic stress” to describe such morphogenetic unbalance [79, 83]. Other sutures in paleoanthropology are used as phylogenetic traits, because they are supposed to be less influenced by environmental factors. This is the case of the “false” suture between the temporal squama and the parietal bone [84, 85]. This suture is sensitive to the general cranial shape and has been used to characterize the cranial form in archaic human species like Homo erectus, which shows a peculiar flattened profile of this element [86]. As a matter of fact, the shape of the temporal squama is widely used in paleoanthropology for systematic and taxonomic purposes. Recently, a delayed fusion of the metopic suture—a character associated with the human genus—has been described in the Taung child, a young Australopithecus africanus of 3– 4 years old. This species, found in South Africa, is dated to 2– 3 million years ago [87]. Regardless of whether this trait can be associated with cranial adjustments, brain reorganization, or factors associated with brain size and obstetric constraints, the timing of closure of the metopic suture reveals some underlying morphogenetic changes at the frontal bone occurring very early in the natural history of hominids. Nowadays, in zoology and anthropology, the role of the sutures within the cranial structural dynamics is largely investigated through computer modeling, most of all through finite-element analysis [88]. Cranial elements are modeled using digital reconstructions, and the propagation

Fig. 5 Despite that genetic changes can alter the suture patterns of the vault, brain growth and development are the main determinants of neurocranial morphogenesis. This image shows an individual with an additional and extremely large bregmatic bone [106]. The presence of a brand new independent ossification centre did not modify the overall cranial organization. The digital reconstruction on the right shows the specimen in perspective, and the position of the bregmatic bone relative to the endocranial space (in red), which suggests a normal brain geometry (bb bregmatic bone; cs coronal suture; fb frontal bone; pb parietal bone; ss sagittal suture)

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Fig. 6 The Neanderthal specimen Saccopastore 1 is dated to about 120,000 years before present, and it displays in rear view many supernumerary ossicles along the lambdoid suture (original photograph courtesy of G. Manzi; drawing after [79])

and effects of the application of forces (i.e., pressures, strains, torsions) are investigated by taking into account the mechanical properties of bone elements and sutures. Sutures are also sensitive to the influence of muscular environments [89], and hence such studies are very useful when dealing with species relying on large muscle loads and bite force like reptiles and dinosaurs [90, 91]. Studies are often aimed at investigating the relationships between cranial sutures, ecology, and diet. In fact, primates harbor speciesspecific characters associated with sutures relating to food consumption and muscle development [92]. Relationships between sutures and morphogenesis still remain somewhat obscure, and most hypotheses still need experimental validation. It is very difficult to understand which traits are causative and which traits are consequences within the cranial functional matrix. Although sutures may have a direct role in shaping the cranial phenotype [93], the

relationship between sutural strains and osteoblast activity is not well known, and other factors (i.e., angiogenic tensions or mechanotransduction) may be relevant to the final coordination between these elements [94]. What is clear is that sutures are now considered not merely as passive elements of the skull, but as important structural components of the cranial functional network.

Fractal geometry of cranial sutures Most of the difficulties in studying the morphological variation of the cranial sutures are related to their irregular shape and missing anatomical references preventing proper quantification in a comparative context. Differences in the degree of expression of these characters and the possibility of different anatomical combinations often hamper the

Fig. 7 Throughout ontogeny, sutures become more and more convoluted, revealing pseudo-fractal properties (after [75] for gentle concession of T. Miura)

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application of traditional statistical approaches. Indeed, these characters tend to represent simultaneous elements of continuous, ordinal, and nominal variables. These limits make results sensitive to methodological choices and biases associated with incomplete (or even incorrect) numerical descriptions. It is also worth noting that such challenges in classifying the variations of sutures in a rigorous and homogeneous way has resulted in the generation of a heterogeneous and inconstant terminology, further limiting a proper flow of information between researchers. Since the introduction of fractal geometry by Benoît Mandelbrot (1924–2010) [95], fractal analysis has emerged as a new tool for the assessment of geometrical complexity shown by natural structures, with many applications in biomedical sciences [96]. In geometrical terms, cranial sutures resemble fractal structures (Fig. 7). Fractal approaches cannot supply information on the shape of the sutural pattern, which must be investigated with different methods [74]. Nonetheless, fractal geometry is able to quantify the degree of complexity and the space-filling properties of the suture morphology. Studies highlight that fractal geometry may be of help not only to investigate changes in suture morphology throughout ontogeny and differences between sexes or ethnic groups, but also to model suture formation. Cranial sutures resemble irregular curves, which may vary locally from nearly straight lines to extremely convoluted sinusoids or even loops [96]. Cranial sutures vary from simple wavy sutures to complex folded ones, and in rare instances evolve and develop into the self-similar, scaling, elaborate ones called intricate sutures [97]. The fractal dimension of sutures summarizes in one parameter the level of geometrical complexity of the structure. A number of methods have been proposed to estimate the fractal dimension of cranial sutures [97–101]. Fractal dimension has been used to quantify the roughness of the nasal suture in order to discriminate male and female skulls in forensic anthropology [102]. In this case, box-counting method was used to quantify the degree of sutural convolution, evidencing the hyperostotic condition of the male cranial architecture. Relationships between muscle local effects and suture morphology have been evidenced through fractal approaches [103]. However, there are still considerable discrepancies in the results obtained by different authors, with the suggested fractal dimension ranging from physically impossible values below 1.0 up to values above 1.6 [98]. Gorski and Skrzat [96] recently proposed that one important factor in these differences is the use of “black box” commercial software to estimate fractal dimension. They investigated the fractal property of cranial sutures using their own box-counting code, focusing on fitting the regression line in the log–log plot. In addition, they determined whether the cranial sutures are monofractal, multi-fractal or non-fractal structures,

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and estimated the fractal dimensions of the coronal and sagittal sutures. According to Long and Long [97], intricate sagittal sutures show 2–3 orders of self-similarity in a wavy line and yield fractal dimensions of about 1.3–1.4. In addition to previous studies on the complexity of sagittal sutures, their findings confirmed this observation [98, 100, 101, 104]. Lynnerup and Jacobsen [119] found that mean fractal dimensions were relatively low for coronal sutures (1.106 for female skulls, 1.118 for male skulls) and sagittal sutures (1.049 for female skulls, 1.161 for male skulls). In contrast, Gorski and Skrzat found the mean fractal dimensions for these two types of sutures to be significantly higher (1.48 and 1.56 for coronal and sagittal sutures respectively, estimated for both sexes together). These differences have been ascribed to differences in the choice of points for the regression line in the box-counting algorithm. Gorski and Skrzat demonstrated that cranial sutures are geometrically monofractal objects with their fractal dimension oscillating around 1.5. It is indubitable that the fractal structure of a cranial suture is mainly due to the spatial organization of minute bony projections, which arise from the edges of the bones, i.e., frontal and parietal bones. Visual inspection of the coronal and sagittal sutures reveals a non-uniform character of the suture interdigitation and various distributions of the bony projections along the course of the suture. There are segments of the suture that only slightly resemble a sinusoidal line, whereas the rest of the suture may be extremely convoluted. This makes it difficult to visually score overall complexity, or to compare such irregular patterns of different skulls. Although more extensive investigation of fractal exponents of sutures is necessary, with special attention to the linear fits in the log–log plots, the fractal dimension is a promising quantitative measure of suture morphology. Cranial suture waveform pattern, or complexity, of vault sutures has frequently been related to mechanical loads resulting from mastication. If true, then one would expect age-related changes in suture complexity to occur as an individual grows in size, with greater loads placed on its masticatory apparatus. In this regard, the quantification of ontogenetic suture complexity remains incomplete. Lynnerup and Jacobsen [98] have investigated whether the fractal dimension, relying on the whole suture length, may provide a superior description of age-related changes in suture morphology, as opposed to other methods of quantification, which generally rely on more arbitrary scoring systems. The authors conclude that until a better understanding of suture biology is reached, cranial sutures are rendered only marginally useful in age determination. Further investigations should hopefully elucidate a more unbiased method of sutural morphology quantification. Suture cells exist in a tightly controlled cycle of proliferation, trans-differentiation/migration, and cell death as orchestrated in large part by the dura mater. Byron in 2006

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investigated the role of bone resorption in defining interdigitations characteristic of cranial suture waveforms. His study, in a mouse model, was aimed at testing the hypothesis that suture complexity increases with age and that bone resorption along concave suture margins by osteoclasts participates in this patterning. He used a combined morphometric and histological approach in an ontogenetic series of mice as well as in bisphosphonate-treated versus control age groups. There was a significant positive relationship observed between suture complexity and osteoclast count within alendronate and control mice, supporting a mechanistic role for osteoclasts in suture morphology. Specifically, osteoclasts show greatest activity along concave suture regions at 42 and 84 days. This coincides with significant incremental increases in suture complexity as measured with fractal dimension at 42 and 84 days of age. In congruence with these data, mice given osteoclast-depleting injections of alendronate show a decrease in sagittal suture complexity [74]. The way in which a fractal structure is generated remains a very interesting issue. It has been reported that interdigitation has a non-integer fractal dimension in the human skull [105]. Although the sutural pattern has been frequently compared with the typical Koch curve, introduced by the Swedish mathematician Niels Fabian Helge von Koch (1838–1913), their relationship remains still poorly understood. It is undeniable, however, that the study of fractal properties of cranial sutures promises to add new perspectives to the comprehension of the mechanisms generating the cranial sutures and to their morphological classification. In addition, the significance of the actual findings suggest that sutural morphogenesis can be described as a repeated iteration function, and mathematical models can be constructed to produce self-similar curves with a proper fractal dimension. This may help elucidate the mechanism of actual pattern formation.

Conclusion Historical findings and records provided the basis for past research, which in turn established a foundation for current studies to further our understanding of cranial sutures. Advancements in biology, anatomy, and mathematics, applied both individually and in combination, have greatly contributed to our current knowledge. To find treatments for the aforementioned anomalies, it is imperative that a holistic view is well understood, as modern innovation requires a multidisciplinary approach. Functional craniology and morphological integration provide the theoretical framework to integrate anatomy and evolution. Computed models supply the tools to evaluate structures and processes. Together, these fields represent a major revolution for anthropology and biomedicine.

Childs Nerv Syst (2013) 29:893–905 Acknowledgments We are grateful to Giorgio Manzi, Luca Bondioli, Fabrizio Barberini, Christoph Zollikofer and Takashi Miura for supplying images and drawings.

References 1. Dimopoulos VG, Kapsalakis IZ, Fountas KN (2007) Skull morphology and its neurosurgical implications in the hippocratic era. Neurosurg Focus 23:E10 2. Greenblatt S (1997) The historiography of neurosurgery: Organizing themes and methodological issues. In: T Dagi, M Epstein (eds) A history of neurosurgery: in its scientific and professional contexts. Thieme Medical Publishers, U.S.A., p 3. 3. The Canon on Medicine, United States National Library of Medicine 4. McVaugh M (2006) The rational surgery of the middle ages. Sismel, Florence 5. Di Ieva A, Tschabitscher M, Prada F et al (2007) The neuroanatomical plates of Guido da Vigevano. Neurosurg Focus 23:E15 6. Di Ieva A, Gaetani P, Matula C et al (2011) Berengario da Carpi: a pioneer in neurotraumatology. J Neurosurg 114:1461–1470 7. Lind R (1975) Studies in Pre-Vesalian Anatomy: Biography, Translations, Documents. American Philosophical Society, Philadelphia 8. Frassanito P, Di Rocco C (2011) Depicting cranial sutures: a travel into the history. Childs Nerv Syst 27:1181–1183 9. Slater BJ, Kwan MD, Gupta DM et al (2008) Dissecting the influence of regional dura mater on cranial suture biology. Plast Reconstr Surg 122:77–84 10. Raam MS, Solomon BD, Shalev SA et al (2010) Holoprosencephaly and craniosynostosis: a report of two siblings and review of the literature. Am J Med Genet C Semin Med Genet 154C:176–182 11. Tubbs RS, Bosmia AN, Cohen-Gadol AA (2012) The human calvaria: a review of embryology, anatomy, pathology, and molecular development. Childs Nerv Syst 28:23–31 12. Ito Y, Yeo JY, Chytil A et al (2003) Conditional inactivation of Tgfbr2 in cranial neural crest causes cleft palate and calvaria defects. Development 130:5269–5280 13. Lana-Elola E, Rice R, Grigoriadis AE et al (2007) Cell fate specification during calvarial bone and suture development. Dev Biol 311:335–346 14. Chai Y, Jiang X, Ito Y et al (2000) Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis. Development 127:1671–1679 15. Jiang X, Rowitch DH, Soriano P et al (2000) Fate of the mammalian cardiac neural crest. Development 127:1607–1616 16. Jiang X, Iseki S, Maxson RE et al (2002) Tissue origins and interactions in the mammalian skull vault. Dev Biol 241:106–116 17. Öcal E, Sun PP, Persing JA (2007) Craniosynostosis. In: Albright AL, Adelson PD, Pollack IF (eds) Principles and practice of pediatric neurosurgery, 2nd edn. Thieme, New York, pp 265–288 18. Morriss-Kay GM, Wilkie AO (2005) Growth of the normal skull vault and its alteration in craniosynostosis: insights from human genetics and experimental studies. J Anat 207:637–653 19. Tholpady SS, Freyman TF, Chachra D et al (2007) Tensional forces influence gene expression and sutural state of rat calvariae in vitro. Plast Reconstr Surg 120:601–11, discussion 612-3 20. Ogle RC, Tholpady SS, McGlynn KA et al (2004) Regulation of cranial suture morphogenesis. Cells Tissues Organs 176:54–66 21. Smith DW, Tondury G (1978) Origin of the calvaria and its sutures. Am J Dis Child 132:662–666 22. Opperman LA (2000) Cranial sutures as intramembranous bone growth sites. Dev Dyn 219:472–485

Childs Nerv Syst (2013) 29:893–905 23. Drake DB, Persing JA, Berman DE et al (1993) Calvarial deformity regeneration following subtotal craniectomy for craniosynostosis: a case report and theoretical implications. J Craniofac Surg 4:85–9, discussion 90 24. Hobar PC, Schreiber JS, McCarthy JG et al (1993) The role of the dura in cranial bone regeneration in the immature animal. Plast Reconstr Surg 92:405–410 25. Hobar PC, Masson JA, Wilson R et al (1996) The importance of the dura in craniofacial surgery. Plast Reconstr Surg 98:217–225 26. Bradley JP, Levine JP, Blewett C et al (1996) Studies in cranial suture biology: in vitro cranial suture fusion. Cleft Palate Craniofac J 33:150–156 27. Opperman LA, Sweeney TM, Redmon J et al (1993) Tissue interactions with underlying dura mater inhibit osseous obliteration of developing cranial sutures. Dev Dyn 198:312–322 28. Opperman LA, Persing JA, Sheen R et al (1994) In the absence of periosteum, transplanted fetal and neonatal rat coronal sutures resist osseous obliteration. J Craniofac Surg 5:327–332 29. Levine JP, Bradley JP, Roth DA et al (1998) Studies in cranial suture biology: regional dura mater determines overlying suture biology. Plast Reconstr Surg 101:1441–1447 30. Chandran S, Lim MK, Yu VY (2000) Fetal acalvaria with amniotic band syndrome. Arch Dis Child Fetal Neonatal Ed 82:F11–3 31. Bialek P, Kern B, Yang X et al (2004) A twist code determines the onset of osteoblast differentiation. Dev Cell 6:423–435 32. Chen L, Li D, Li C et al (2003) A Ser252Trp [corrected] substitution in mouse fibroblast growth factor receptor 2 (Fgfr2) results in craniosynostosis. Bone 33:169–178 33. Lee MS, Lowe GN, Strong DD et al (1999) TWIST, a basic helixloop-helix transcription factor, can regulate the human osteogenic lineage. J Cell Biochem 75:566–577 34. Ting MC, Wu NL, Roybal PG et al (2009) EphA4 as an effector of Twist1 in the guidance of osteogenic precursor cells during calvarial bone growth and in craniosynostosis. Development 136:855–864 35. Yousfi M, Lasmoles F, El Ghouzzi V et al (2002) Twist haploinsufficiency in saethre-chotzen syndrome induces calvarial osteoblast apoptosis due to increased TNFalpha expression and caspase-2 activation. Hum Mol Genet 11:359–369 36. Yousfi M, Lasmoles F, Lomri A et al (2001) Increased bone formation and decreased osteocalcin expression induced by reduced twist dosage in saethre-chotzen syndrome. J Clin Invest 107:1153–1161 37. Hajihosseini MK (2008) Fibroblast growth factor signaling in cranial suture development and pathogenesis. Front Oral Biol 12:160–177 38. Loeys BL, Chen J, Neptune ER et al (2005) A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 37:275–281 39. Klein R (2004) Eph/ephrin signaling in morphogenesis, neural development and plasticity. Curr Opin Cell Biol 16:580– 589 40. Kullander K, Klein R (2002) Mechanisms and functions of eph and ephrin signalling. Nat Rev Mol Cell Biol 3:475–486 41. Wilkinson DG (2001) Multiple roles of EPH receptors and ephrins in neural development. Nat Rev Neurosci 2:155–164 42. Jabs EW, Muller U, Li X et al (1993) A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis. Cell 75:443–450 43. Kim HJ, Rice DP, Kettunen PJ et al (1998) FGF-, BMP- and shhmediated signalling pathways in the regulation of cranial suture morphogenesis and calvarial bone development. Development 125:1241–1251 44. Merrill AE, Bochukova EG, Brugger SM et al (2006) Cell mixing at a neural crest-mesoderm boundary and deficient ephrin-eph signaling in the pathogenesis of craniosynostosis. Hum Mol Genet 15:1319–1328

903 45. Podesta PG, Negretto A, Vecchi De J, Villigran R, Montaldo A, Benedek P, Hornblas JJ (1985) Management of a complex case of Crouzons syndrome. In: Marchac D (ed) Craniofacial surgery. Springer, Berlin Heidelberg New York, pp 160–162 46. Shillito J Jr (1992) A plea for early operation for craniosynostosis. Surg Neurol 37:182–188 47. McComb JG (1981) Treatment of functional lambdoid synostosis. Neurosurg Clin N Am 2:665–672 48. Matson DD (1969) Neurosurgery of Infancy and Childhood (2nd ed). Charles C Thomas Publisher, Springfield 49. Epstein N, Epstein F, Newman G (1982) Total vertex craniectomy for the treatment of scaphocephaly. Childs Brain 9:309–316 50. Thaller SR, Hoyt J, Boggan J (1992) Surgical correction of unilateral lambdoid synostosis: occipital rotation flap. J Craniofac Surg 3:12–7, discussion 18-9 51. Vander Kolk CA, Carson BS, Robertson BC et al (1993) The occipital bar and internal osteotomies in the treatment of lambdoidal synostosis. J Craniofac Surg 4:112–118 52. Pollack IF, Losken HW, Fasick P (1997) Diagnosis and management of posterior plagiocephaly. Pediatrics 99:180–185 53. Marchac D, Renier D (1982) Craniofacial surgery for craniosynostosis. Little, Brown, Boston, Massachusetts 54. Jimenez DF, Barone CM (1998) Endoscopic craniectomy for early surgical correction of sagittal craniosynostosis. J Neurosurg 88:77–81 55. Jimenez DF, Barone CM, Cartwright CC et al (2002) Early management of craniosynostosis using endoscopic-assisted strip craniectomies and cranial orthotic molding therapy. Pediatrics 110:97–104 56. Barone CM, Jimenez DF (2004) Endoscopic approach to coronal craniosynostosis. Clin Plast Surg 31:415–22, vi 57. Murad GJ, Clayman M, Seagle MB et al (2005) Endoscopicassisted repair of craniosynostosis. Neurosurg Focus 19:E6 58. Hinojosa J, Esparza J, Munoz J (2007) Endoscopic-assisted osteotomies from the treatment of craniosysnostis. Childs Nerv Syst 23:1421–1430 59. Jimenez DF, Barone CM (2010) Multiple-suture nonsyndromic craniosynostosis: early and effective management using endoscopic techniques. J Neurosurg Pediatr 5:223–231 60. Hanihara T, Ishida H (2001) Os incae: variation in frequency in major human population groups. J Anat 198:137–152 61. Hauser G, De Stefano G (1989) Epigenetic variants of the human skull. Schweizerbart, Stuttgart 62. Wang Q, Opperman LA, Havill LM et al (2006) Inheritance of sutural pattern at the pterion in rhesus monkey skulls. Anat Rec A Discov Mol Cell Evol Biol 288:1042–1049 63. Meindl RS, Lovejoy CO (1985) Ectocranial suture closure: a revised method for the determination of skeletal age at death based on the lateral-anterior sutures. Am J Phys Anthropol 68:57–66 64. Krogman WM, Iscan MY (1986) The human skeleton in forensic medicine (2nd edn). Charles C Thomas Publishers, Springfield 65. Mann RW, Symes SA, Bass WM (1987) Maxillary suture obliteration: aging the human skeleton based on intact or fragmentary maxilla. J Forensic Sci 32:148–157 66. Buikstra JE, Ubelaker DH (1994) Standards for data collection from human skeletal remains: Proceedings of a Seminar at the Field Museum of Natural History. Arkansas Archaeological Survey Press, Fayetteville 67. Enlow DH (1966) A comparative study of facial growth in Homo and Macaca. Am J Phys Anthropol 24:293–308 68. Duterloo HS, Enlow DH (1970) A comparative study of cranial growth in Homo and Macaca. Am J Anat 127:357–368 69. Collins HB (1925) The pterion in primates. Am J Phys Anthropol 8:261–274

904 70. Ashley-Montagu MG (1933) The anthropological significance of the pterion in the primates. Am J Phys Anthropol 18:159–336 71. Bruner E, Mantini S, Manzi G (2004) A geometric morphometric approach to airorhynchy and functional cranial morphology in Alouatta (Atelidae, Primates). J Anthropol Sci 82:47–66 72. Moss ML, Young RW (1960) A functional approach to craniology. Am J Phys Anthropol 18:281–292 73. Bruner E (2007) Cranial shape and size variation in human evolution: structural and functional perspectives. Childs Nerv Syst 23:1357–1365 74. Zollikofer CP, Weissmann JD (2011) A bidirectional interface growth model for cranial interosseous suture morphogenesis. J Anat 219:100–114 75. Miura T, Perlyn CA, Kinboshi M et al (2009) Mechanism of skull suture maintenance and interdigitation. J Anat 215:642–655 76. Anton SC, Jaslow CR, Swartz SM (1992) Sutural complexity in artificially deformed human (Homo sapiens) crania. J Morphol 214:321–332 77. White CD (1996) Sutural effects of fronto-occipital cranial modification. Am J Phys Anthropol 100:397–410 78. O’Loughlin VD (2004) Effects of different kinds of cranial deformation on the incidence of wormian bones. Am J Phys Anthropol 123:146–155 79. Manzi G (2003) “Epigenetic” cranial traits, Neandertals and the origin of Homo sapiens. Riv Antropol 81:57–68 80. Bruner E (2004) Geometric morphometrics and paleoneurology: brain shape evolution in the genus Homo. J Hum Evol 47:279– 303 81. Sergi S (1934) Ossicini fontanellari della regione del lambda nel cranio di Saccopastore e nei crani neandertaliani. Riv Antropol 30:101–112 82. Sergi S (1948) L’uomo di Saccopastore. Paleontographia Italica XLII:25–164 83. Manzi G, Vienna A, Hauser G (1996) Developmental stress and cranial hypostosis by epigenetic trait occurrence and distribution: an exploratory study on the Italian Neandertals. J Hum Evol 30:511–527 84. Harvati K (2003) Quantitative analysis of Neanderthal temporal bone morphology using three-dimensional geometric morphometrics. Am J Phys Anthropol 120:323–338 85. Terhune CE, Kimbel WH, Lockwood CA (2007) Variation and diversity in Homo erectus: a 3D geometric morphometric analysis of the temporal bone. J Hum Evol 53:41–60 86. Terhune CE, Deane AS (2008) Temporal squama shape in fossil hominins: relationships to cranial shape and a determination of character polarity. Am J Phys Anthropol 137:397–411 87. Falk D, Zollikofer CP, Morimoto N et al (2012) Metopic suture of taung (Australopithecus africanus) and its implications for hominin brain evolution. Proc Natl Acad Sci U S A 109:8467–8470 88. Kupczik K (2008) Virtual biomechanics: basic concepts and technical aspects of finite element analysis in vertebrate morphology. J Anthropol Sci 86:193–198 89. Herring SW, Teng S (2000) Strain in the braincase and its sutures during function. Am J Phys Anthropol 112:575–593 90. Rayfield EJ (2005) Using finite-element analysis to investigate suture morphology: a case study using large carnivorous dinosaurs. Anat Rec A Discov Mol Cell Evol Biol 283:349–365 91. Moazen M, Curtis N, O’Higgins P et al (2009) Assessment of the role of sutures in a lizard skull: a computer modelling study. Proc Biol Sci 276:39–46 92. Byron CD (2009) Cranial suture morphology and its relationship to diet in Cebus. J Hum Evol 57:649–655 93. Enlow DH (1990) Facial Growth. WB Saunders Company, Philadelphia

Childs Nerv Syst (2013) 29:893–905 94. Henderson JH, Longaker MT, Carter DR (2004) Sutural bone deposition rate and strain magnitude during cranial development. Bone 34:271–280 95. Mandelbrot BB (1983) The Fractal Geometry of Nature. Freeman, San Francisco 96. Gorski AZ, Skrzat J (2006) Error estimation of the fractal dimension measurements of cranial sutures. J Anat 208:353–359 97. Long CA, Long JE (1992) Fractal dimensions of cranial sutures and waveforms. Acta Anat (Basel) 145:201–206 98. Lynnerup N, Jacobsen JC (2003) Brief communication: age and fractal dimensions of human sagittal and coronal sutures. Am J Phys Anthropol 121:332–336 99. Tsonis AA, Tsonis PA (1987) Fractals: a new look at biological shape and patterning. Perspect Biol Med 30:355–361 100. Skrzat J, Walocha J (2003) Fractal dimensions of the sagittal (interparietal) sutures in humans. Folia Morphol (Warsz) 62:119–122 101. Yu JC, Wright RL, Williamson MA et al (2003) A fractal analysis of human cranial sutures. Cleft Palate Craniofac J 40:409–415 102. Schiwy-Bochat KH (2001) The roughness of the supranasal region—a morphological sex trait. Forensic Sci Int 117:7–13 103. Monteiro LR, Lessa LG (2000) Comparative analysis of cranial suture complexity in the genus Caiman (Crocodylia, Alligatoridae). Braz J Biol 60:689–694 104. Hartwig WC (1991) Fractal analysis of sagittal suture morphology. J Morphol 210:289–290 105. Long CA (1985) Intricate sutures as fractal curves. J Morphol 185:285–295 106. Barberini F, Bruner E, Cartolari R et al (2008) An unusually-wide human bregmatic wormian bone: anatomy, tomographic description, and possible significance. Surg Radiol Anat 30:683–687 107. Howard TD, Paznekas WA, Green ED et al (1997) Mutations in TWIST, a basic helix-loop-helix transcription factor, in saethrechotzen syndrome. Nat Genet 15:36–41 108. Sood S, Eldadah ZA, Krause WL et al (1996) Mutation in fibrillin-1 and the marfanoid-craniosynostosis (shprintzen-goldberg) syndrome. Nat Genet 12:209–211 109. Twigg SR, Kan R, Babbs C et al (2004) Mutations of ephrin-B1 (EFNB1), a marker of tissue boundary formation, cause craniofrontonasal syndrome. Proc Natl Acad Sci U S A 101:8652–8657 110. Jenkins D, Seelow D, Jehee FS et al (2007) RAB23 mutations in carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity. Am J Hum Genet 80:1162–1170 111. Kamath BM, Stolle C, Bason L et al (2002) Craniosynostosis in alagille syndrome. Am J Med Genet 112:176–180 112. Yen HY, Ting MC, Maxson RE (2010) Jagged1 functions downstream of Twist1 in the specification of the coronal suture and the formation of a boundary between osteogenic and non-osteogenic cells. Dev Biol 347:258–270 113. Yu HM, Jerchow B, Sheu TJ et al (2005) The role of Axin2 in calvarial morphogenesis and craniosynostosis. Development 132:1995–2005 114. Ishii M, Merrill AE, Chan YS et al (2003) Msx2 and twist cooperatively control the development of the neural crestderived skeletogenic mesenchyme of the murine skull vault. Development 130:6131–6142 115. Dodig M, Tadic T, Kronenberg MS et al (1999) Ectopic Msx2 overexpression inhibits and Msx2 antisense stimulates calvarial osteoblast differentiation. Dev Biol 209:298–307 116. Liu YH, Tang Z, Kundu RK et al (1999) Msx2 gene dosage influences the number of proliferative osteogenic cells in growth centers of the developing murine skull: a possible mechanism for MSX2mediated craniosynostosis in humans. Dev Biol 205:260–274

Childs Nerv Syst (2013) 29:893–905 117. Maxson R, Ishii M, Merrill A (2003) Murine Homeobox Gene Control of Embryonic Patterning and Organogenesis. Elsevier Science, New York 118. Li C, Scott DA, Hatch E et al (2007) Dusp6 (Mkp3) is a negative feedback regulator of FGF-stimulated ERK signaling during mouse development. Development 134:167–176 119. Settle SH Jr, Rountree RB, Sinha A et al (2003) Multiple joint and skeletal patterning defects caused by single and double mutations in the mouse Gdf6 and Gdf5 genes. Dev Biol 254:116–130

905 120. Moenning A, Jager R, Egert A et al (2009) Sustained plateletderived growth factor receptor alpha signaling in osteoblasts results in craniosynostosis by overactivating the phospholipase Cgamma pathway. Mol Cell Biol 29:881–891 121. Zhang X, Kuroda S, Carpenter D et al (2002) Craniosynostosis in transgenic mice overexpressing nell-1. J Clin Invest 110:861–870 122. Stone DM, Hynes M, Armanini M et al (1996) The tumoursuppressor gene patched encodes a candidate receptor for sonic hedgehog. Nature 384:129–134