The axial skeleton includes the skull, vertebral column, ribs, and sternum. In general, the skeletal system develops from paraxial and lateral plate (parietal layer) mesoderm and from neural crest. Paraxial mesoderm forms a segmented series of tissue blocks on each side of the neural tube, known as somitomeres in the head region and somites from the occipital region caudally. Somites differentiate into a ventromedial part, the sclerotome, and a dorsolateral part, the dermomyotome. At the end of the fourth week, sclerotome cells become polymorphous and form loosely organized tissue, called mesenchyme, or embryonic connective tissue (Fig. 10.1). It is characteristic for mesenchymal cells to migrate and to differentiate in many ways. They may become fibroblasts, chondroblasts, or osteoblasts (bone-forming cells).
Figure 10.1.Development of the somite.
A. Paraxial mesoderm cells are arranged around a small cavity. B. As a result of further differentiation, cells in the ventromedial wall lose their epithelial arrangement and become mesenchymal. Collectively, they are called the sclerotome. Cells in the ventrolateral and dorsomedial regions form muscle cells and also migrate beneath the remaining dorsal epithelium (the dermatome) to form the myotome.
The bone-forming capacity of mesenchyme is not restricted to cells of the sclerotome, but occurs also in the parietal layer of the lateral plate mesoderm of the body wall. This layer of mesoderm forms bones of the pelvic and shoulder girdles, limbs, and sternum (see Chapter 12). Neural crest cells in the head region also differentiate into mesenchyme and participate in formation of bones of the face and skull.
The remainder of the skull is derived from occipital somites and somitomeres. In some bones, such as the flat bones of the skull, mesenchyme in the dermis differentiates directly into bone, a process known as intramembranous ossification (Fig. 10.2). In most bones, however, including the base of the skull and the limbs, mesenchymal cells first give rise to hyaline cartilage models, which in turn become ossified by endochondral ossification (Fig. 10.3). The following paragraphs discuss development of the most important bony structures and some of their abnormalities.
Figure 10.2.Skull bones of a 3-month-old fetus show the spread of bone spicules from primary ossification centers in the flat bones of the skull.
Figure 10.3.Endochondral bone formation.
A. Mesenchyme cells begin to condense and differentiate into chondrocytes. B. Chondrocytes form a cartilaginous model of the prospective bone. C,D. Blood vessels invade the center of the cartilaginous model, bringing osteoblasts (black cells) and restricting proliferating chondrocytic cells to the ends (epiphyses) of the bones. Chondrocytes toward the shaft side (diaphysis) undergo hypertrophy and apoptosis as they mineralize the surrounding matrix. Osteoblasts bind to the mineralized matrix and deposit bone matrices. Later, as blood vessels invade the epiphyses, secondary ossification centers form. Growth of the bones is maintained by proliferation of chondrocytes in the growth plates
The skull can be divided into two parts: the neurocranium, which forms a protective case around the brain, and the viscerocranium, which forms the skeleton of the face.
The neurocranium is most conveniently divided into two portions: (1) the membranous part, consisting of flat bones, which surround the brain as a vault, and (2) the cartilaginous part, or chondrocranium, which forms bones of the base of the skull.
The membranous portion of the skull is derived from neural crest cells and paraxial mesoderm as indicated in Figure 10.4. Mesenchyme from these two sources invests the brain and undergoes intramembranous ossification. The result is formation of a number of flat, membranous bones that are characterized by the presence of needle-like bone spicules. These spicules progressively radiate from primary ossification centers toward the periphery (Fig. 10.2). With further growth during fetal and postnatal life, membranous bones enlarge by apposition of new layers on the outer surface and by simultaneous osteoclastic resorption from the inside.
Figure 10.4.Skeletal structures of the head and face.
Mesenchyme for these structures is derived from neural crest (blue), paraxial mesoderm (somites and somitomeres) (red), and lateral plate mesoderm (yellow)
At birth, the flat bones of the skull are separated from each other by narrow seams of connective tissue, the sutures, which are also derived from two sources: neural crest cells (sagittal suture) and paraxial mesoderm (coronal suture). At points where more than two bones meet, sutures are wide and are called fontanelles (Fig. 10.5). The most prominent of these is the anterior fontanelle, which is found where the two parietal and two frontal bones meet. Sutures and fontanelles allow the bones of the skull to overlap (molding) during birth. Soon after birth, membranous bones move back to their original positions, and the skull appears large and round. In fact, the size of the vault is large compared with the small facial region (Fig. 10.5B).
Figure 10.5.Skull of a newborn, seen from above A and the right side B.
Note the anterior and posterior fontanelles and sutures. The posterior fontanelle closes about 3 months after birth; the anterior fontanelle closes around the middle of the second year. Many of the sutures disappear during adult life
Several sutures and fontanelles remain membranous for a considerable time after birth. The bones of the vault continue to grow after birth, mainly because the brain grows. Although a 5- to 7-year-old child has nearly all of his or her cranial capacity, some sutures remain open until adulthood. In the first few years after birth, palpation of the anterior fontanelle may give valuable information as to whether ossification of the skull is proceeding normally and whether intracranial pressure is normal. In most cases, the anterior fontanelle closes by 18 months of age, and the posterior fontanelle closes by 1 to 2 months of age.
Cartilaginous Neurocranium or Chondrocranium
The cartilaginous neurocranium or chondrocranium of the skull initially consists of a number of separate cartilages. Those that lie in front of the rostral limit of the notochord, which ends at the level of the pituitary gland in the center of the sella turcica, are derived from neural crest cells. They form the prechordal chondrocranium. Those that lie posterior to this limit arise from occipital sclerotomes formed by paraxial mesoderm and form the chordal chondrocranium. The base of the skull is formed when these cartilages fuse and ossify by endochondral ossification (Figs. 10.3 and 10.6).
Figure 10.6.Dorsal view of the chondrocranium, or base of the skull, in the adult showing bones formed by endochondral ossification.
Bones that form rostral to the rostral half of the sella turcica arise from neural crest and constitute the prechordal (in front of the notochord) chondrocranium (blue). Those forming posterior to this landmark arise from paraxial mesoderm (chordal chondrocranium) (red).
The viscerocranium, which consists of the bones of the face, is formed mainly from the first two pharyngeal arches (see Chapter 17). The first arch gives rise to a dorsal portion, the maxillary process, which extends forward beneath the region of the eye and gives rise to the maxilla, the zygomatic bone, and part of the temporal bone (Fig. 10.7). The ventral portion, the mandibular process, contains the Meckel cartilage. Mesenchyme around the Meckel cartilage condenses and ossifies by intramembranous ossification to give rise to the mandible. The Meckel cartilage disappears except in the sphenomandibular ligament. The dorsal tip of the mandibular process, along with that of the second pharyngeal arch, later gives rise to the incus, the malleus, and the stapes (Fig. 10.7). Ossification of the three ossicles begins in the fourth month, making these the first bones to become fully ossified. Mesenchyme for formation of the bones of the face is derived from neural crest cells, including the nasal and lacrimal bones (Fig. 10.4).
Figure 10.7.Lateral view of the head and neck region of an older fetus, showing derivatives of the arch cartilages participating in formation of bones of the face
At first, the face is small in comparison with the neurocranium. This appearance is caused by (1) virtual absence of the paranasal air sinuses and (2) the small size of the bones, particularly the jaws. With the appearance of teeth and development of the air sinuses, the face loses its babyish characteristics.
Craniofacial Defects and Skeletal Dysplasias
Neural Crest Cells
Neural crest cells originating in the neuroectoderm form the facial skeleton and part of the skull. These cells also constitute a vulnerable population as they leave the neuroectoderm; they are often a target for teratogens. Therefore, it is not surprising that craniofacial abnormalities are common birth defects (see Chapter 17).
In some cases, the cranial vault fails to form (cranioschisis), and brain tissue exposed to amniotic fluid degenerates, resulting in anencephaly. Cranioschisis is caused by failure of the cranial neuropore to close (Fig. 10.8A). Children with such severe skull and brain defects cannot survive. Children with relatively small defects in the skull through which meninges and/or brain tissue herniate (cranial meningocele and meningoencephalocele, respectively) (Fig. 10.8B) may be treated successfully. In such cases, the extent of neurological deficits depends on the amount of damage to brain tissue
Figure 10.8.A. Child with anencephaly.
Cranial neural folds fail to elevate and fuse, leaving the cranial neuropore open. The skull never forms, and brain tissue degenerates. B. Patient with meningocele. This rather common abnormality may be successfully repaired.
Another important category of cranial abnormalities is caused by premature closure of one or more sutures. These abnormalities are collectively known as craniosynostosis, which occurs in one in 2,500 births and is a feature of more than 100 genetic syndromes. The shape of the skull depends on which of the sutures closed prematurely. Early closure of the sagittal suture (57% of cases) results in frontal and occipital expansion, and the skull becomes long and narrow (scaphocephaly) (Fig. 10.9). Premature closure of the coronal sutures results in a short skull called brachycephaly (Fig. 10.10A). If the coronal sutures close prematurely on one side only, then the result is an asymmetric flattening of the skull called plagiocephaly (Fig. 10.10B,C). Regulation of suture closure involves secretion of various isoforms of transforming growth factor-?.
Figure 10.9.Craniosynostosis involving the sagittal suture.
A. Child with scaphocephaly caused by early closure of the sagittal suture. Note the long narrow shape of the head with prominent frontal and occipital regions. B,C computed tomography (CT) scans of the skull showing the long narrow shape of the head with bossing of the frontal and occipital regions. B. caused by premature closure of the sagittal suture C
Figure 10.10.Craniosynostosis involving the coronal sutures.
A. Child with brachycephaly caused by early closure of both coronal sutures. Note the tall shape of the skull with flattened frontal and occipital regions. B. Child with plagiocephaly resulting from premature closure of the coronal suture on one side of the skull. C. CT scan of the skull showing plagiocephaly resulting from premature closure of the coronal suture on one side.
Fibroblast growth factors (FGFs) and fibroblast growth factor receptors (FGFRs) also play important roles in skeletal development. There are many members of the FGF family and their receptors. Together, they regulate cellular events, including proliferation, differentiation, and migration. Signaling is mediated by the receptors, which are transmembrane tyrosine kinase receptors, each of which has three extracellular immunoglobulin domains, a transmembrane segment, and a cytoplasmic tyrosine kinase domain. FGFR1 and FGFR2 are coexpressed in prebone and precartilage regions, including craniofacial structures; FGFR3 is expressed in the cartilage growth plates of long bones and in the occipital region. In general, FGFR2 increases proliferation, and FGFR1 promotes osteogenic differentiation, whereas the role of FGFR3 is unclear.
Mutations in these receptors, which often involve only a single amino acid substitution, have been linked to specific types of craniosynostosis (FGFr1, FGFR2, and FGFR3) and several forms of Skeletal dysplasia (FGFR3) (Table 10.1). In addition to these genes, mutations in the transcription factor MSX2, a regulator of parietal bone growth, causes Boston-type craniosynostosis, which can affect a number of bones and sutures. The TWIST1 gene codes for a DNA-binding protein and plays a role in regulating proliferation. Mutations in this gene cause Saethre–Chotzen’s syndrome characterized by proliferation and premature differentiation in the coronal suture, causing craniosynostosis, and syndactyly (Fig. 10.10).
Table 10.1.Genes Associated with Skeletal Defects
|FGFR1||8p12||Pfeiffer’s syndrome||Craniosynostosis, broad great toes and thumbs, cloverleaf skull, underdeveloped face|
|Apert’s syndrome||Craniosynostosis, underdeveloped face, symmetric syndactyly of hands and feet|
|Jackson–Weiss’s syndrome||Craniosynostosis, underdeveloped face, foot anomalies, hands usually spared|
|Crouzon’s syndrome||Craniosynostosis, underdeveloped face, no foot or hand defects|
|FGFR3||4p16||Achondroplasia (ACH)||Short-limb dwarfism, underdeveloped face|
|Thanatophoric dysplasia (type I)||Curved short femurs, with or without cloverleaf skull|
|Thanatophoric dysplasia (type II)||Relatively long femurs, severe cloverleaf skull|
|Hypochondroplasia||Milder form of ACH with normal craniofacial features|
|TWIST||7p21||Saethre–Chotzen’s syndrome||Craniosynostosis, midfacial hypoplasia, cleft palate, vertebral anomalies, hand and foot abnormalities|
|HOXA13||Hand-foot-genital syndrome||Small, short digits, divided uterus, hypospadias|
|HOXD13||2q31||Synpolydactyly||Fused, multiple digits|
|TBX5||12q24.1||Upper limb and heart defects||Digit defects, absent radius, limb bone hypoplasia, atrial and ventricular septal defects, conduction abnormalities|
|COLIA1 and COLIA2||Limb defects, blue sclera||Shortening, bowing, and hypomineralization of the long bones, blue sclera|
|Fibrillin (FBNI)||15q15-21||Marfan’s syndrome||Long limbs and face, sternal defects (pectus excavatum and carinatum), dilation and dissection of the ascending aorta, lens dislocation|