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LIMBS

Limb Growth and Development

Limbs buds appear in the fourth week.

1. Lateral plate mesoderm forms the bonesand connective tissue,

2. somites form the muscles of the limbs.

Gene regulation:The AER gene regulates limb outgrowth,and the ZPA gen controls anteroposterior

patterning.

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Development of the limb buds in human embryos.A. At 5 weeks. B. At 6 weeks. C. At 8 weeks.

B. Hindlimb development lags behind forelimb

development by 1 to 2 days.

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Longitudinal section through the limb bud showing a core ofmesenchyme covered by a layer of ectoderm that thickens atthe distal border of the limb to form the apical ectodermalridge. In humans, this occurs during the fifth week ofdevelopment.

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Schematic of human

hands.

A.At 48 days. Cell

death in the apicalectodermal ridge

creates a separate

ridge for each digit.

B. At 51 days. Cell death

in the interdigital

spaces produces

separation of thedigits.

C. At 56 days. Digit

separation is

complete.

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Lower extremity of

an early 6-weekembryo,illustrating the

first hyalinecartilage models.

B,C. Complete set

of cartilagemodels at theend of the 6th

week

And the beginningof the 8th week,respectively.

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Endochondral boneformation.

A. Mesenchyme cells begin

to condense anddifferentiate intochondrocytes.

B. Chondrocytes form a

cartilaginous model ofthe prospective bone.

C,D. Blood vessels invadethe center of thecartilaginous model,

bringing osteoblasts(black cells) andrestricting proliferatingchondrocytic cells to theends (epiphyses) of thebones.

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Molecular regulationof patterning andgrowth in the limb.

A. Limb outgrowth isinitiated by FGF10secreted by lateral

plate mesoderm inthe limb-forming

regions.Once outgrowth is

initiated, the apicalectodermal ridge isinduced by bone

morphogeneticproteins and restrictedin its location by thegene Radical fringeexpressed in dorsal

ectoderm.

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Chondrocytes towardthe shaft side(diaphysis) undergohypertrophy and

apoptosis as theymineralize thesurrounding matrix.

Osteoblasts bind to themineralized matrixand deposit bonematrices. Later, asblood vessels invadethe epiphyses,

secondary ossificationcenters form.

Growth of the bones ismaintained by

proliferation of

chondrocytes in therowth lates

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In turn, this expressioninduces that ofSER2incells destined to form theapical ectodermal ridge.

After the ridge isestablished, it expressesFGF4 and FGF8 tomaintain the progresszone, the rapidly

proliferating mesenchymecells adjacent to the ridge.

B.Anteroposteriorpatterningof the limb is

controlled by cells in thezone of polarizing activityat the posterior border.

These cells produce

retinoic acid (vitamin A),

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These cells produce retinoic acid (vitamin A),which initiates expression ofsonic hedgehog,regulating patterning.

C.The dorsoventral limb axis expressed in thedorsal ectoderm.

D. Bone type and shape are regulated by clusters

of genes , they are the primary determinants ofbone morphology.

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Experimental procedure forgrafting a new zone of

polarizing activity fromone limb bud into another

using chick embryos.

The result is the productionof a limb with mirrorimage duplication of the

digits indicating therole of the zone ofpolarizing activity inregulatinganteroposterior

patterning of the limb.Sonic hedgehogprotein is

the molecule secreted bythe zone of polarizingactivity responsible for thisregulation.

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Clinical CorrelatesBone Age

1) Radiologists use the appearance of variousossification centers to determine whether a childhas reached his or herproper maturation age.

2) Useful information about bone age is obtainedfrom ossification studies in the hands and wristsof children.

3) Prenatal analysis of fetal bones byultrasonography provides information about fetalgrowth and gestational age.

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Limb Defects

Limb malformations occur in approximately6\10,000 live births,

with 3.4 \10,000 affecting the upper limbs

and 1.1 \10,000 affecting the lower limbs.

These defects are often associated with otherbirth defects involving the

1) craniofacial,2) cardiac,

3) and genitourinary systems.

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Abnormalities of the limbs

1) partial absence of one or more of theextremities (meromelia)

2) complete absence (amelia) of one or moreof the extremities

3) Sometimes the long bones are absent, andrudimentary hands and feet are attached tothe trunk by small, irregularly shapedbones (phocomelia, a form of meromelia)

4) Sometimes all segments of the extremitiesare present but abnormally short(micromelia).

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Hhhhcfzs

ade7y8uiop[;

Child withunilateral ameliaand multipledefects of theleft upper limb.

B. Patient with aform of

meromelia calledphocomelia. Thehands areattached to thetrunk by

irregularlyshaped bones.

i l h di

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mainly hereditary,

cases of teratogen-induced limb defects have beendocumented.. Many mothers of these infants had takenthalidomide, a drug widely used as a sleeping pill and

antinauseant.thalidomide causes a characteristic syndrome of

malformations consisting of

1. absence or gross deformities of the long bones,

2. intestinal atresia.3. cardiac anomalies.

Because the drug is now being used to treat AIDS andcancer patients, there is concern that its return will result

in a new wave of limb defects.

Studies indicate that the most sensitive period forteratogen-induced limb malformations is the fourth and

fifth weeks of development.

A diff f li b d f i l

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A different category of limb defects involvesthe digits.

Sometimes the digits are shortened(brachydactyly);

If two or more fingers or toes are fused, it is calledsyndactyly

Normally, mesenchyme between prospective digits inhand- and footplates is removed by cell death(apoptosis). In one \2,000 births this process fails, andthe result is fusion between two or more digits.

The presence of extra fingers or toes is calledpolydactylyThe extra digits frequently lack propermuscle connections. Abnormalities involving polydactylyare usually bilateral,

whereas absence of a digit (ectrodactyly), such as a

thumb, usually occurs unilaterally.

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Digital defects.A.Brachydactyly, short

digits

.B. Syndactyly, fused

digits.

C. Polydactyly, extradigits.

D. Cleft foot, lobster

claw deformity.

Any of these defectsmay involve either the

hands or feet or both.

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A number of gene mutations have been

identified that affect the limbs and sometimes

other structuresResult in

1-hand-foot-genital syndrome

2-Holt-Oram syndrome.

3-Osteogenesis imperfecta5-Clubfoot .

6-Congenital absence or deficiency of the radius .

7-craniosynostosis-radial aplasia syndrome

8-Congenital hip dislocation

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VERTEBRAE AND THE VERTEBRAL

COLUMN

Thevertebral column andribsdevelop from the

sclerotome

compartments of thesomites,

and the sternum is derivedfrom mesoderm in the

ventral body wall.

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A definitive

vertebrais formed by

condensation of

the caudal half of

one sclerotome and

fusion with thecranial half of the

subjacent

sclerotome

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The many abnormalities of the skeletal

system include

1. vertebral (spina bifida),

2. cranial (cranioschisis and craniosynostosis),

3. facial (cleft palate) defects.

Major malformations of the limbs are rare, but

defects of the radius and digits are oftenassociated with other abnormalities

(syndromes).

A h b f i f

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As the vertebrae form, twoprimary curves of

the spine are established:

1. the thoracic curvature2. The sacral curvature.

Later, two secondary curves are established:1-cervical curvature , asthe child learns to hold up

his or her head

2- the lumbar curvature ,which forms when the

child learns to walk.

V t b l D f t

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Vertebral DefectsScoliosis(lateral curving of the spine).

When two successive vertebrae fuse asymmetrically orhave half a vertebra missing, a cause of scoliosis

(spina bifida),One of the most serious vertebral defects is the result of

imperfect fusion or nonunion of the vertebral arches.Such an abnormality, known as cleft vertebra (spinabifida),

(1-spina bifida occulta).involve only the bony vertebral arches, leaving the spinal

cord intact. the bony defect is covered by skin, and no

neurological deficits occur (spina bifida occulta).

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2-spina bifida cysticaA more severe abnormality in which the neural tube

fails to close, vertebral arches fail to form, andneural tissue is exposed, Any neurological deficitsdepend on the level and extent of the lesion

This defect,

1. which occurs in one per 1,000 births,

2. may be prevented, in many cases, by providingmothers with folic acid prior to conception.

3. Spina bifida can be detected prenatally byultrasound, and if neural tissue is exposed,amniocentesis can detect elevated levels of -fetoprotein in the amniotic fluid.

RIBS

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RIBS:1-The bony portion of each ribis derived

from sclerotome cells that remain in theparaxialmesoderm and that grow out from the costal

processes of thoracic vertebrae.

2-Costal cartilages are formed by sclerotome cells that migrate across the

lateral somitic frontier into the adjacent lateral platemesoderm

The sternumdevelops independently in lateral plate mesoderm in the

ventral body wall.

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Rib Defects

Clinical Correlates.Cervical ribs

occur in approximately 1% of the populationand are usually attached to the seventhcervical vertebra. Because of its location,this type of rib may impinge on the brachial

plexus or the subclavian artery, resulting invarying degrees of anesthesia in the limb.

Defect of the Stern m

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Defects of the Sternum1-Cleft sternum

is a very rare defect and may be complete or located ateither end of the sternum.

Thoracic organs are covered only by skin and soft tissue.The defect arises when the sternal bands fail to growtogether in the midline.

2- Hypoplastic ossification centers

3- premature fusion of sternal segmentsalso occur particularly in infants with congenital heart defects (20%

to 50%)

4- Multiple manubrial ossification centers occur in 6% to 20%of all children but are especially common in those with Downsyndrome

Pectus excavatum

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Pectus excavatum

is the term for a depressed sternum that issunken posteriorly.

Pectus carinatum

refers to a flattening of the chest bilaterallywith an anteriorly projecting sternum.

. Both defects may result from abnormalitiesof ventral body wall closure or formation ofthe costal cartilages and sternum

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