‫بسم هللا الرحمن الرحيم‬

Medical embryology
limbs
By
Dr. Marwa Mahmood
second Stage
2024-2025
 Limb growth and development

• At the end of the 4th week of development, limb buds become visible as outpocketings
from the ventrolateral body wall. The forelimb appears first followed by the hindlimb 1
to 2 days later.

• Initially, the limb buds consist of a mesenchymal core derived from the parietal
(somatic) layer of lateral plate mesoderm that will form the bones and connective
tissues of the limb, covered by a layer of cuboidal ectoderm.

• Ectoderm at the distal border of the limb thickens and forms the apical ectodermal
ridge (AER). This ridge exerts an inductive influence on next by mesenchyme
remain undifferentiated, rapidly proliferating cells, the progress zone.
• As the limb grows, cells farther from the influence of the AER begin to differentiate into
cartilage and muscle. In this manner, development of the limb proceeds proximodistally.
• In 6-week-old embryos, the terminal portion of the limb buds becomes flattened to
form the hand- and footplates and is separated from the proximal segment by a circular
constriction. Later, a second constriction divides the proximal portion into two
segments, and the main parts of the extremities can be recognized.

• Fingers and toes are formed when cell death in the AER separates this ridge into five
parts. Further formation of the digits depends on (1) their continued outgrowth under
the influence of the five segments of ridge ectoderm, (2) condensation of the
mesenchyme to form cartilaginous digital rays, (3)the death of intervening tissue
between the rays.

• Development of the upper and lower limbs is similar except that:

(1) morphogenesis of the lower limb is approximately 1 to 2 days behind that of the
upper limb.
(2) Upper limb buds lie opposite the lower five cervical and upper two thoracic segments),
and the lower limb buds lie opposite the lower four lumbar and upper two sacral
segments.
(3) during the 7th week of gestation, the limbs rotate in opposite directions. The upper limb
rotates 90° laterally, so that the extensor muscles lie on the lateral and posterior
surface, and the thumbs lie laterally, whereas the lower limb rotates approximately 90
degrees medially, placing the extensor muscles on the anterior surface and the big toe
medially.
 Endochondral ossification
• While the external shape is being established, mesenchyme in the buds begins to
condense, and these cells differentiate into chondrocytes. By the sixth week of
development, the first hyaline cartilage models, foreshadowing the bones of the
extremities, are formed by these chondrocytes.

• Ossification of the bones of the extremities, endochondral ossification, begins by the

end of the embryonic period. Primary ossification centers are present in all long bones
of the limbs by the 12th week of development. From the primary center in the shaft or
diaphysis of the bone, endochondral ossification gradually progresses toward the ends
of the cartilaginous model. At birth, the diaphysis of the bone is usually completely
ossified, but the two ends, the epiphyses, are still cartilaginous. Shortly thereafter,
ossification centers arise in the epiphyses. Temporarily, a cartilage plate remains
between the diaphyseal and epiphyseal ossification centers. This plate, the epiphyseal
plate, plays an important role in growth in the length of the bones. Endochondral
ossification proceeds on both sides of the plate. When the bone has acquired its full
length, the epiphyseal plates disappear, and the epiphyses unite with the shaft of the
bone.
• In long bones, an epiphyseal plate is found on each extremity; in smaller bones, such as
the phalanges, it is found only at one extremity; and in irregular bones, such as the
vertebrae, one or more primary centers of ossification and usually several secondary
centers are present.
Joints

Joints are formed in the cartilaginous condensations when chondrogenesis is arrested, and a
joint interzone is induced. Cells in this region increase in number and density, and then a
joint cavity is formed by cell death. Surrounding cells differentiate into a joint capsule
(mesenchyme cells surrounding the interzone region). Factors regulating the positioning of
joints are not clear, but the secreted molecule WNT14 appears to be the inductive signal.
 Limb musculature

Limb musculature is derived from cells of the somites that migrate into the limb to form
muscles and, initially, these muscle components are segmented according to the somites
from which they are derived. However, with elongation of the limb buds, the muscle tissue
first splits into flexor and extensor components and then additional splittings and fusions
occur, such that a single muscle may be formed from more than one original segment. The
resulting complex pattern of muscles is determined by connective tissue derived from
lateral plate mesoderm.

Upper limb buds lie opposite the lower five cervical and upper two thoracic segments), and
the lower limb buds lie opposite the lower four lumbar and upper two sacral segments. As
soon as the buds form, ventral primary rami from the appropriate spinal nerves penetrate
into the mesenchyme. At first, each ventral ramus enters with dorsal and ventral branches
derived from its specific spinal segment, but soon branches in their respective divisions
begin to unite to form large dorsal and ventral nerves. Thus, the radial nerve, which sup-
plies the extensor musculature, is formed by a combination of the dorsal segmental
branches, whereas the ulnar and median nerves, which supply the flexor musculature, are
formed by a combination of the ventral branches. Immediately after the nerves have
entered the limb buds, they establish an intimate contact with the differentiating
mesodermal condensations, and the early contact between the nerve and muscle cells is a
prerequisite for their complete functional differentiation. Spinal nerves not only play an
important role in differentiation and motor innervation of the limb musculature, but also
provide sensory innervation for the dermatomes. Although the original dermatomal pattern
changes with growth and rotation of the extremities, an orderly sequence can still be
recognized in the adult.
 Clinical correlates

Bone age:

Radiologists use the appearance of various ossification centers to determine whether a child
reached his or her proper maturation age,( e.g. the hands and wrists bones).

Limbs defects

Limbs malformations often associated with other birth defects including the craniofacial,
cardiac, and genitourinary systems.

Meromelia: partial absence of one or more of extremities.

Amelia: complete absence of one or more of extremities.

Micromelia: all segments of extremities are present but abnormally short.

Phocomelia: is a rare congenital anomaly where the proximal aspect of an extremity is

absent with the hand or foot attached directly to the trunk. It was a characteristic
side effect of the drug thalidomide but can occur spontaneously.

Thalidomide (a sleeping pill and antinauseant) causes syndromes of malformations:

absence or cross abnormalities of the long bones, intestinal atresia, and cardiac
anomalies. 4th and 5th weeks are the most sensitive period for limb defects.
Thalidomide is now used to treat AIDS and cancer patients.

Brachydactyly: short digits.

Syndactyly: two or more fingers or toes are fused. Normally, mesenchyme between the
digits in hands and footplates is removed by cell death (apoptosis).
Polydactyly: the presence of extra fingers or toes, usually lack proper muscle connections
and usually bilateral.
Ectrodactyly: absence of a digit (e.g. the thumb).

Cleft hand and foot: consists of an abnormal cleft between the second and fourth bones and
soft tissues. The third bone is almost always absent, and the thumb and index fingers and
the 4th and 5th fingers may be fused. The two parts of the hands are somewhat opposed to
each other.

Osteogenesis imperfecta

Is characterized by shortening, bowing, and hypomineralization of the long bones of the

limbs that can result in fractures and blue sclera. Several types of OI ranging from repeated
fractures to be lethal during neonatal period. Most of cases are caused by mutations in the
COL1A1 or COL1A2 genes. These genes code for type 1 collagen, the most abundant
collagen in the human body. It is found in bones, tendons and ligaments.
Amniotic band syndrome, also known as constriction ring syndrome, the origin not clear but
other investigators believe that may happens when fibrous bands of the amniotic sac (the
lining inside the uterus that contains a fetus) get tangled around a developing fetus. May
resulted in an amputation of the limb or the digits.

Congenital dislocation or subluxation of the hip (congenital acetabular dysplasia) is a

complete or partial displacement of the femoral head out of the acetabulum. Most common
in female, the dislocation appears after birth although the defect occurs prenatally. Because
most of the cases associated with breech delivery, it has been thought that breech
presentation may be interfere with hip development. It is frequently associated with laxity
of the ligaments.