Hairs develop during the fetal period as proliferations of the stratum germinativum of the epidermis growing into the underlying dermis. The tip of the hair bud becomes a hair bulb and is soon invaginated by the mesenchymal hair papilla in which the vessels and nerve endings develop (Fig. 4.2A, B). The epidermal cells in the centre of the hair bud become keratinized to form the hair shaft, and the surrounding mesenchymal cells differentiate into the dermal root sheath (Fig. 4.2C). Small bundles of smooth muscle fibres called arrector pili muscles develop in the mesenchyme and are attached to the dermal sheath (Fig. 4.2C). Most sebaceous glands develop as buds from the side of the epithelial root sheath growing into the dermis; these glands produce an oily secretion that lubricates the hair and skin. The sweat glands develop as epidermal buds into the underlying dermis which become coiled to form the secretory part of the glands (Fig. 4.2C).

Fig. 4.2 Development of the hair, arrector pili muscle, sebaceous and sweat glands at (A) 14 weeks, (B) 24 weeks and (C) in the newborn.

Mammary glands and teeth

The mammary glands arise from a pair of epidermal thickenings called mammary ridges which appear in both sexes during the fourth week from the axilla to the inguinal region (Fig. 4.3A). Normally these ridges disappear except in the pectoral region where breasts develop, but part of the mammary ridges may persist to form an extra breast (polymastia) or supernumary breasts and nipples (Fig. 4.3A). The breast develops from a primary mammary bud which gives rise to several secondary buds that form the lactiferous ducts and their branches. The buds branch throughout the fetal period, become canalized and open into a small depression called the mammary pit of the nipple (Fig. 4.3B, C).

Fig. 4.3 Development of the mammary glands in (A) showing the location of the mammary ridges and common formation sites of supernumerary breasts and nipples at (B) 7 weeks and (C) 8 months.

The teeth develop as tooth buds from the epithelial lining of the oral cavity along a U-shaped epidermal ridge called the dental lamina along the curves of the upper and lower jaws. The ectodermal tooth bud grows into the neural crest-derived mesenchyme, and passes through a ‘cap’ and a ‘bell’ stage. The enamel is produced by ameloblasts which are derived from the ectoderm; the underlying dentin and other tissues are derived from the mesenchyme and neural crest cells.

The musculoskeletal system

The mesenchyme gives rise to the musculoskeletal system. Most of the mesenchyme is derived from the mesodermal cells of the somites and the somatopleuric layer of lateral plate mesoderm (see Chapter 1). The mesenchyme in the head region comes from the neural crest cells. Regardless of their sources, a common feature of mesenchymal cells is their ability to migrate and differentiate into many different cell types, e.g. myocytes, fibroblasts, chondroblasts or osteoblasts. This differentiation often requires interaction with either epithelial cells or the components of the surrounding extracellular matrix.

The skeletal system

The origin of mesenchymal cells forming the skeletal tissues varies in different regions of the body. Mesenchymal cells forming the axial skeleton arise from the mesodermal somites, whereas the bones of the appendicular skeleton are derived from the somatopleuric mesenchyme of the lateral plate mesoderm. After reaching their destination the mesenchymal cells condense and form models of bones. The subsequent differentiation of mesenchymal cells into chondroblasts or osteoblasts is genetically controlled. Various molecular processes, therefore, play a significant role in determining whether mesenchymal cells undergo a membranous ossification or transform into cartilage models, which later become ossified by endochondral ossification.

Development of the axial skeleton

The axial skeleton is composed of the skull, vertebral column, sternum and ribs. This part of the skeleton is derived from the paraxial mesoderm, which is soon organized into the somites. The first somites appear on day 20 in the cranial region, and by 30 days approximately 37 pairs are formed. Somites appear as rounded elevations under the surface ectoderm on the dorsal aspect of the embryo from the base of the skull to the tail region. Each somite subdivides into two parts: the sclerotome and the dermomyotome (Fig. 4.4). The cells of the sclerotome give rise to the vertebrae and ribs, and those of the dermomyotome form muscle and the dermis of the skin.

Fig. 4.4 Differentiating somites in a 4-week embryo.

The vertebral column

The development of the vertebral column passes through three stages. Vertebrae begin as mesenchymal condensations around the notochord, which then transform into cartilaginous models. From the sixth week the ossification of vertebrae begins and usually ends by the twenty-fifth year of life.

During the initial mesenchymal stage, the sclerotome cells migrate medially towards the notochord, and meet the sclerotome cells from the other side to form the centrum or vertebral body. Each sclerotome splits into a cranial and a caudal segment (Fig. 4.5A). The cranial half of the sclerotome consists of loosely arranged cells, whereas the caudal half contains densely packed cells. The caudal half of a sclerotome fuses with the cranial half of the sclerotome below to form the vertebral body (Fig. 4.5B). From the vertebral body, sclerotome cells move dorsally and surround the developing spinal cord to form the vertebral arch. In each vertebra, the costal and transverse processes develop from the vertebral arches. The vertebral arches of each vertebra join dorsally to form the spinous processes. The formation of the vertebral body is dependent on inducing substances produced by the notochord, and that of the vertebral arch, on the interaction of sclerotome cells with the surface ectoderm.

Fig. 4.5 Diagrams of a 4-week embryo showing the formation of vertebral column from sclerotomes (A, B). In (A) the direction of migration of sclerotome cells is indicated by arrows.

The intervertebral disc has an outer collagenous annulus fibrosus and a central gelatinous core, the nucleus pulposus (Fig. 4.6). The annulus fibrosus develops from the densely packed lower portion of the sclerotome, whereas the nucleus pulposus is derived from the notochord. The rest of the notochord at the level of the vertebral bodies soon disappears.

Fig. 4.6 Adult vertebrae and the position of spinal nerves and intersegmental vessels.

Because of its formation from two sclerotomes on each side, a vertebra is intersegmental in origin. However, the spinal nerves are segmental as they emerge at the level of the corresponding somite in close relationship to the intervertebral discs.

Clinical box

A spina bifida occulta (see Chapter 10 and Fig. 10.5A) may occur when the two halves of the vertebral arch fail to fuse behind the spinal cord. This minor anomaly usually occurs in the lumbosacral region, often marked by a patch of hairy skin overlying the affected area, and is often first identified on routine radiological examination.

The notochordal tissue may persist and give rise to chordomas. Most chordomas occur in the midline, most commonly at the base of the skull or in the sacrococcygeal region. These tumours may become malignant, and infiltrate the surrounding bones, occurring more commonly in males and rarely before the age of 30 years.

Sternum and ribs

The sternum develops from a pair of cartilaginous bars that form in the ventral body wall. These bars fuse in the midline in a craniocaudal sequence to form the manubrium and the body of the sternum (Fig. 4.7). The anomaly of cleft sternum would occur if the two sternal bars fail to unite, and may present as a circular defect in the sternum, often an incidental finding at a radiological examination. The ribs arise from the costal processes of the vertebrae in the thoracic region. These become cartilaginous, grow laterally toward the sternum, and become ossified. At other vertebral levels the costal processes do not grow distally but are incorporated into the transverse processes of the vertebrae.

Fig. 4.7 Development of the sternum and ribs between 42 and 45 days.

Clinical box

Elongation of lower cervical or upper lumbar costal processes gives rise to accessory ribs. A cervical rib is attached to the seventh cervical vertebra, and may exert pressure on the brachial plexus or the subclavian artery. The cervical rib often produces motor, sensory and autonomic disturbances in the hand due to nerve compression. Symptoms arise most commonly in the fourth decade of life, and factors such as trauma or poor posture may be predisposing.

Skull

The skull is composed of the neurocranium, which surrounds the brain, and the viscerocranium, which surrounds the mouth, pharynx and larynx. Each of these divisions develops by endochondral or intramembranous ossification. The bones of the neurocranium at the cranial base develop from occipital sclerotomes as three pairs of cartilages, whereas the flat bones of the skull cap develop directly from mesenchyme derived from the neural crest.

The bones of the cranial vault are thin at birth and are separated by fibrous tissue called sutures. The areas where more than two bones meet the unossified mesenchyme are known as fontanelles (Fig. 4.8). Six fontanelles are present at birth but the anterior and posterior fontanelles are most obvious. The growth of the brain is accompanied by expansion of skull bones, and both continue to grow during fetal life and early childhood. Not only do the sutures and fontanelles allow skull bones to expand but the fontanelles also override each other during birth to allow the fetal head to pass through the birth canal. Most of the fontanelles disappear during the first year because of growth of surrounding bones, but the anterior fontanelle remains membranous until 18 months after birth.

Fig. 4.8 The fetal skull. (A) Superior view. (B) Lateral view.

The skeleton of the viscerocranium is derived from the first two pharyngeal arches, which support the jaws (see Chapter 11). The mesenchyme in these arches condenses to form a rod of cartilage surrounded by perichondrium. Some of the perichondrium from the pharyngeal arches gives rise to ligaments attached to the skull, and most of the cartilage is replaced by membranous bone. The body and ramus of the mandible develops from the mesenchyme around the ventral end of the first pharyngeal arch cartilage (Meckel’s cartilage). The condyle and the chin area of the mandible ossify by the process of endochondral ossification. The ear ossicles, the hyoid bone and laryngeal cartilages are also derived from the cartilaginous bars of pharyngeal arches (see Chapter 11).

Clinical box

Most skull deformities result from abnormal development of the brain or from premature closure of some sutures. Babies born with acrania (absence of calvaria) fail to survive because most of the brain is absent. In microcephaly, the size of the brain is very small, and consequently the skull fails to grow. The cranial abnormality of craniosynostosis results from premature closure of the skull sutures. The external appearance of the head depends upon which sutures close early. For example, if the sagittal suture closes early, the skull becomes long and narrow, resulting in a condition referred to as scaphocephaly.

The appearance of the anterior fontanelle can be used to assess whether normal skull ossification is occurring, or to identify the presence of raised intracranial pressure (because the fontanelle bulges).

Development of the limbs and appendicular skeleton

The ectodermal cells at the most distal part of the limb bud form the apical ectodermal ridges. These ectodermal ridges induce the proliferation and differentiation of the underlying mesenchyme, thus forming a rapidly elongating limb precursor. The upper limb buds appear between day 24 and 26 at the level of the fifth to eighth cervical segments, whereas the lower limb buds form opposite the third to fifth lumbar segments at about 28 days. As the limb buds elongate, the distal ends of the limb buds become flattened to form hand and footplates. As this growth proceeds the more distal parts differentiate into cartilage and muscle.

The appendicular skeleton consists of the limb girdles and the bones of the limbs. The bones of the appendicular skeleton develop from mesenchymal condensations which become cartilaginous models (Fig. 4.9). The clavicle is the only exception, which begins as a model membranous bone. The centres of ossification first appear in the limb bones during the eighth week. By the twelfth week, the shafts of the limb bones are ossified, though the carpal bones of the wrist remain cartilaginous until after birth. The ossification of the three largest tarsal bones of the ankle begins at about 16 weeks, but some of the smaller tarsal bones do not ossify until 3 years after birth.

Fig. 4.9 Developing limb skeleton. (A) Upper limb 5 weeks. (B) Lower limb 8 weeks.

In a typical long bone of a limb, the ossification process begins in the shaft or diaphysis, where the cartilage cells enlarge and the extracellular matrix becomes calcified. From this primary centre of ossification, the bone develops towards the ends of the cartilaginous model. A nutrient artery nourishes the central region of the developing bone by penetrating the cartilage. At birth the shafts of long bones are completely ossified, but the ends of the bones or epiphyses are still cartilaginous. During the first few years after birth, secondary ossification centres appear in the epiphyses, and bone formation continues in all directions. However, a band of cartilage, the epiphyseal growth or cartilaginous plate, remains between the two centres of ossification. The cells of the epiphyseal plate remain active until the long bone ceases to grow, and once the epiphyseal plate becomes ossified to unite with the shaft of the bone, growth is no longer possible. You should refer to an histology textbook for details of histogenesis of bones such as ICT Histology.

Joints form from the mesenchyme between the developing bones. In a synovial joint, the mesenchymal tissue breaks down to form a cavity, whereas in fibrous and cartilaginous joints, the mesenchyme differentiates into either dense fibrous tissue or cartilage.

Clinical box

Anomalies of limbs result from a combination of genetic and environmental factors, or teratogenic effects of drugs, or simply mechanical factors. Some deformities involving digits, such as polydactyly, syndactyly and lobster claw hand or foot, arise as a result of genetic mutations. Other anomalies, such as talipes equinovarus or clubfoot, and dysplasia of joints, have been attributed to mechanical compression of the fetus against the uterine wall. Amniotic bands also can produce unwanted pressure on developing limbs, resulting in constrictions or even complete amputations. This direct pressure on the fetal body may be due to the condition of oligohydramnios where the volume of amniotic fluid is too little. Failure of the kidneys to develop may cause oligohydramnios.

The muscular system

Skeletal muscles develop from the myoblasts derived from the somites, with the exception of much of the head musculature, which is derived from the pharyngeal arches or the neural crest mesenchyme (see Chapter 11). The muscles of the neck and trunk are derived from the myotomes, whereas the limb musculature develops from myogenic cells that migrate from the ventrolateral region of the dermomyotome of the somite.

Each myotome divides into a dorsal epimere and a ventral hypomere (Fig. 4.10). The epimere gives rise to the back muscles, including the erector spinae, whereas the hypomere forms the lateral and ventral muscles of the thorax and abdomen. The muscles derived from the hypomere include the intercostal muscles in the thorax, the three layers of the anterior abdominal wall, the rectus abdominis and the infrahyoid muscles. The spinal nerves divide into dorsal and ventral rami supplying each division of the myotome. The dorsal rami innervate the muscles derived from the epimeres, and the ventral rami innervate the muscles derived from the hypomeres.