Appendages - Overview
The appendicular skeleton is the skeleton of the upper and lower limbs.
• In the upper limb, the bones include: clavicle, scapula, humerus, radius and ulna, 8 carpals, 5 metacarpals and 16 phalanges.
• In the lower limb, the bones include: hip bone (pelvic girdle), femur, tibia and fibula, 7 tarsals, 5 metatarsals and 16 phalanges.
These bones arise from lateral plate mesoderm that migrates into the limb buds to form cartilage models. The models subsequently undergo endochondral ossification, except for the clavicle, which develops by intramembranous ossification.
Limb Buds
Limb buds make their appearance in the 4th week.
Their placement is determined by HOX genes with the upper limb bud appearing in the cervical region around day 24 and the lower limb bud in the lumbar region around day 28.
By 5 weeks they are distinct features of the embryo.
Each limb bud possesses a core of mesoderm and a covering of surface ectoderm.
At the tip of each limb bud is a thick apical ectodermal ridge (AER), a signaling center that promotes elongation of the limb buds.
The long axis of the limb bud divides it into preaxial (cranial) and postaxial (caudal) sections.
The zone of polarizing activity (ZPA) on the postaxial side of the limb is a mesodermal signaling center that promotes formation of postaxial (ulnar, fibular) limb structures. The little finger and little toe are on the post axial sides of their respective limbs while the thumb and great toe are preaxial structures.
The cranial side of the limb is preaxial; in front of the midline axis of the limb (closer to the embryo's head).
The caudal side of the limb is postaxial; behind the midline axis of the limb (closer to the embryo's tail).
The distal end of each limb bud develops a paddle shape; hand on the upper limb, foot on the lower limb.
The greater appendage (thumb, big toe) is on the preaxial side and pointing cranially.
HINT: Think of sitting on a sofa with your arms stretched out on the back of the sofa. Your thumbs would point cranially (preaxial ) and your little finger and edge of your hand would rest on the sofa (postaxial).
Patterning of the Limbs
The apical ectodermal ridge (AER), secretes fibroblast growth factors (FGFs), that suppress differentiation of the underlying mesoderm, allowing it to proliferate. This region of rapidly dividing mesoderm cells beneath the AER, the progress zone, adds to the mesodermal core of the limb bud, displacing the AER distally, thus, promoting elongation of the limb bud.
The expression of HOX genes in the mesoderm of the progress zone, determines regionalization of the limb. Longer time in the progress zone means more distal structures will form.
As the suppressive influence of the AER diminishes proximally, the mesoderm begins differentiation in response to retinoid acid. Formation of skeletal elements of the limb proceeds in a proximal to distal sequence.
On the postaxial side of the limb bud, a mesodermal signaling center called the zone of polarizing activity (ZPA) secretes sonic hedgehog (Shh) guiding the development of the postaxial vs preaxial sides of the limb.
In the upper limb, the ulna and little finger are postaxial and the radius and thumb are preaxial.
In the lower limb, the great toe and tibia are preaxial while fibula and little toe are postaxial.
It should be noted that postaxial structures form earlier than preaxial ones.
In Summary:
Gradients of signal molecules from different points in the limb bud combine to guide limb development.
- fibroblast growth factor (fgf)(orange) from AER, maintains mesoderm in an undifferentiated and proliferative state (progress zone)
- retinoic acid (RA)(purple) from proximal mesenchyme of the limb promotes differentiation of skeletal elements
- sonic hedgehog (Shh)(green) from the zone of polarizing activity (ZPA) determines postaxial vs preaxial patterning of the limb.
Mesoderm throughout the limb bud is exposed to microenvironments of unique combinations of these signal molecules driving differentiation into musculoskeletal structures appropriate to their region and position in the limb.
By six-weeks, mesodermal mesenchymal, largely derived from lateral plate mesoderm, begins to form cartilage models of the limb bones.
The preaxial and postaxial patterning of the limb is determined by Sonic hedgehog (Shh) from the zone of polarizing activity (ZPA), which moves distally with elongation of the limb.
Again Note: radius and thumb are preaxial; ulna and little finger are postaxial on the upper limb.
and
tibia and great toe are preaxial; fibula and little toe are postaxial on the lower limb.
The AER is split into 5 segments, each now guiding the development of a digital ray to form the digits.
As the limb nears completion of development, separation of the digits is accomplished by degeneration of the tissue between the digital rays through apoptosis.
Joint Formation
Midline condensations of mesenchyme, largely of lateral plate mesoderm origin, form in the midline of the limb bud.
Initiation of chondrogenesis results in cartilage models of limb bones with breakdown of tissue in presumptive joint spaces.
Surrounding mesoderm forms synovial membrane, CT of joint capsule and ligaments.
Ossification of the skeletal elements begins in utero and continues until the second decade postpartum.
Clinical Correlates
Hand & Foot Deformities
Cleft Foot or Hand
Cleft foot or hand, sometimes called "lobster claw" deformity is a malformation of the hands, feet or both, in which the first and second and fourth and fifth digits are generally fused and the midline of the hand or foot is absent,
It is thought to be caused by loss of the AER over the third digital ray.. It usually affects the hands more frequently than the feet. In this case, both hands and both feet are affected. In the feet it appears that the second toe is missing, with fusion of the three lateral toes.
Case courtesy of Dr Dalia Ibrahim, Radiopaedia.org. From the case rID: 31433
Cleft Foot or Hand
This is an adult patient with bilateral cleft foot that affects the tarsals, metatarsals and phalanges.
Case courtesy of Dr Paul Smith, Radiopaedia.org. From the case rID: 12310
I recall in particular seeing a young man who was promoted as "'The Lobster Boy". Of course, I didn't know it at the time, but he was a person with bilateral clefts of his hands and feet. I saw him a once or twice in the following years at the fair. I was always impressed by the confidence with which he stated, "I am the lobster boy!", as if there were no others and the dexterity with which he used his hands and feet. I believe that was one of the experiences that prompted my interest in Biology and in Development in particular.
Polydactyly
Polydactyly is the presences of more than 5 digits, It is thought to be related to additional splitting of the AER and is usually more apparent on the preaxial (thumb) side or post axial (little finger) side of the hand or foot. Less frequently in the middle of the hand or foot.
Case courtesy of Assoc Prof Frank Gaillard, Radiopaedia.org. From the case rID: 10382
Syndactyly
Syndactyly is the fusion of digits, usually due to failure of apoptosis to occur between digital rays, although it may also involve fusion of the bony elements of the digits.
Syndactyly in this patient is due to the former, though there is evidence of malformation of the middle and distal phalanges of the third digit.
Case courtesy of Dr Abhinav Amarnath Mohan, Radiopaedia.org. From the case rID: 43232
