Embryology of the HandEmbryology of the Hand

Tom W Barwick Tom W Barwick

SpR Trauma and OrthopaedicsSpR Trauma and OrthopaedicsCity Hospitals SunderlandCity Hospitals Sunderland

AimsAims

• Knowledge of early limb Knowledge of early limb development is necessary to development is necessary to understand limb abnormalitiesunderstand limb abnormalities

• Stay awake….Stay awake….

Clinical significanceClinical significance

• 6% births have anomaly; 3% structural6% births have anomaly; 3% structural

• Infant deaths related to congenital Infant deaths related to congenital anomaly in 20%anomaly in 20%

• Limb deficiency in 3-8 per 1000 birthsLimb deficiency in 3-8 per 1000 births

Congenital anomaliesCongenital anomalies

• 10% of all anomalies occur in upper 10% of all anomalies occur in upper limblimb

• Isolated or systemic association (life Isolated or systemic association (life threatening syndromes)threatening syndromes)

• Most occur in the embryonic period (up Most occur in the embryonic period (up to week 8)to week 8)

General termsGeneral terms

• CongenitalCongenital anomaly apparent at birthanomaly apparent at birth

• DevelopmentalDevelopmental deviation occurring over time, may deviation occurring over time, may not not be apparent at birthbe apparent at birth

• MalformationMalformation structure wrongly built; failure of structure wrongly built; failure of embryologic development or embryologic development or

differentiation resulting in abnormal or differentiation resulting in abnormal or missing structuresmissing structures

• DysplasiaDysplasia abnormal or wrongly constructed abnormal or wrongly constructed tissue due to abnormal developmenttissue due to abnormal development

General termsGeneral terms

• DisruptionDisruption a structure undergoing normal a structure undergoing normal development that stops development that stops

developing or is developing or is destroyed or destroyed or removedremoved

• DeformationDeformation normally formed structure that is normally formed structure that is pushed out of shape by pushed out of shape by

mechanical mechanical forcesforces

• DeformityDeformity a body part altered in shape from a body part altered in shape from normal, outside the normal rangenormal, outside the normal range

EmbryogenesisEmbryogenesis

• EmbryonicEmbryonic Fertilisation to 8 weeks Fertilisation to 8 weeks (limb shape is fully (limb shape is fully

formed formed and differentiation and differentiation is is complete)complete)

• FoetalFoetal 8 weeks to birth 8 weeks to birth (growth and (growth and maturation) maturation)

Axial skeletonAxial skeleton

• Skull, vertebrae, ribs and sternumSkull, vertebrae, ribs and sternum

• Derived from sclerotome of somitesDerived from sclerotome of somites

• NotochordNotochord organising structure of axial organising structure of axial skeleton appears @ 15 daysskeleton appears @ 15 days

• SomitesSomites appear either side of notochordappear either side of notochord

(19-32 days)(19-32 days)

• Neural tube closes cranial to caudal by 28 days Neural tube closes cranial to caudal by 28 days (vertebral templates (anlage) present)(vertebral templates (anlage) present)

Appendicular skeletonAppendicular skeleton

• Pectoral and pelvic girdles and limbsPectoral and pelvic girdles and limbs

• Limb bud (Wolff’s crest) appears at 28 daysLimb bud (Wolff’s crest) appears at 28 days

• Surface ectoderm thickens to form Surface ectoderm thickens to form apical apical ectodermal ridge (AER)ectodermal ridge (AER) that guides that guides developmentdevelopment

• Mesoderm = zone of polarising activity (ZPA) Mesoderm = zone of polarising activity (ZPA) and Progress zone (PZ)and Progress zone (PZ)

Limb budLimb bud

TimescaleTimescale

• Day 32 Day 32 hand platehand plate

• 55thth week week cartilage model of bonescartilage model of bones

• Day 41 Day 41 delineation of raysdelineation of rays

• 66thth week week hyaline anlage of proximal hyaline anlage of proximal arm bonesarm bones

• 77thth week week outgrowth and rotationoutgrowth and rotation

• Day 46Day 46 notched rays/digit notched rays/digit

Limb rotational alignmentLimb rotational alignment

• Embryonic periodEmbryonic period 4 limb/ buds have 4 limb/ buds have parallel axesparallel axes

• Pre-axial bordersPre-axial borders Cephalad (thumb)Cephalad (thumb)• Post-axial borders Post-axial borders Caudad (little)Caudad (little)

• Foetal periodFoetal period upper limb rotation occurs upper limb rotation occurs around axis of long fingeraround axis of long finger

• Upper limb rotates 90 degrees Upper limb rotates 90 degrees externallyexternally

TimescaleTimescale

• Day 32 Day 32 hand platehand plate

• 55thth week week cartilage model of bonescartilage model of bones

• Day 41 Day 41 delineation of raysdelineation of rays

• 66thth week week hyaline anlage of proximal hyaline anlage of proximal arm bonesarm bones

• 77thth week week outgrowth and rotationoutgrowth and rotation

• Day 46Day 46 notched rays/digit notched rays/digit

6 week foetus6 week foetus

Timescale Timescale

• Week 8Week 8 digits short and webbeddigits short and webbed

• Week 12Week 12Primary ossification centres Primary ossification centres

• Week 34-38Week 34-38 Secondary oss. CentresSecondary oss. Centres

• Vessels present in mesoderm by week 3Vessels present in mesoderm by week 3

• Primary axial artery; brachialPrimary axial artery; brachial

• Innervation follows and muscle diffnInnervation follows and muscle diffn

What controls growth?What controls growth?

• Homeobox (Hox genes)Homeobox (Hox genes) convey body plan or convey body plan or position information (Hox A/D)position information (Hox A/D)

• Sonic hedgehog (Shh) genesSonic hedgehog (Shh) genes and proteins are and proteins are involved in limb developmentinvolved in limb development

• Retinoic acid regulates cells that produce shh; Retinoic acid regulates cells that produce shh; hox is an intermediatehox is an intermediate

• Shh and hox genes regulate BMP expressionShh and hox genes regulate BMP expression• Conservation across speciesConservation across species

Limb budLimb bud

Apical Ectodermal Ridge Apical Ectodermal Ridge (AER)(AER)• Columnar epitheliumColumnar epithelium• Needed for sustained outgrowth of limb Needed for sustained outgrowth of limb

budbud• Organisational regionOrganisational region• Proximal to distal positional informationProximal to distal positional information• Hox genes may control mass and local Hox genes may control mass and local

mesenchymal condensationmesenchymal condensation• ?Radical fringe gene regulation?Radical fringe gene regulation

Apical Ectodermal RidgeApical Ectodermal Ridge

• FGF produced by AERFGF produced by AER• Apoptosis of webbing to form digits Apoptosis of webbing to form digits

(syndactyly)(syndactyly)• AER Loss leads to amelia AER Loss leads to amelia

• Duration of AER induction/ amount of Duration of AER induction/ amount of mesoderm available/ interaction/ mesoderm available/ interaction/ local growth factors = normal growthlocal growth factors = normal growth

Zone of Polarizing ActivityZone of Polarizing Activity

Zone of Polarizing ActivityZone of Polarizing Activity

• Posterior mesoderm in limb budPosterior mesoderm in limb bud• Sonic hedgehog gene controlSonic hedgehog gene control• Retinoic acid mimics its effectsRetinoic acid mimics its effects• Stimulates FGF production from AERStimulates FGF production from AER• Positive feedbackPositive feedback

• (Putting ZPA on chick abdomen leads to (Putting ZPA on chick abdomen leads to formation of normal wingformation of normal wing

• Transplant ZPA onto pre-axial border leads Transplant ZPA onto pre-axial border leads to duplication of distal elements of limb)to duplication of distal elements of limb)

Progress zoneProgress zone

• Mesoderm beneath AERMesoderm beneath AER

• Undifferentiated cellsUndifferentiated cells

• Orientation and progressionOrientation and progression

• Skeletal positioningSkeletal positioning

• Loss of PZ leads to truncation of limbLoss of PZ leads to truncation of limb

• Thalidomide: abnormal progress zone Thalidomide: abnormal progress zone cellscells

• Excision leads to normal growthExcision leads to normal growth

Limb budLimb bud

Wingless type (Wnt) signalling Wingless type (Wnt) signalling centrecentre

• Located in dorsal Located in dorsal ectodermectoderm

• Wnt-7 gene mediates dorsal to ventral Wnt-7 gene mediates dorsal to ventral axis configuration of mesenchymeaxis configuration of mesenchyme

• Muscle/ tendon derived Muscle/ tendon derived

• Note that muscle and tendon develop Note that muscle and tendon develop separately and connect laterseparately and connect later

• Coordination of signalling centresCoordination of signalling centres

ClassificationsClassifications

• NumerousNumerous

• SwansonSwanson, Barsky and Entin, Barsky and Entin

• Based on embryological failures (7)Based on embryological failures (7)

• InclusiveInclusive

Swanson ClassificationSwanson Classification

1.1.Failure of formationFailure of formation– Transverse deficiencies-any levelTransverse deficiencies-any level– Longitudinal deficiencies; pre-axial, central, post-Longitudinal deficiencies; pre-axial, central, post-

axial, intercalatoryaxial, intercalatory

2.2.Failure of differentiation Failure of differentiation – Soft tissue; syndactyly, trigger finger, Poland Soft tissue; syndactyly, trigger finger, Poland

Syn, camptodactylySyn, camptodactyly– Skeletal; synostoses and carpal coalitionSkeletal; synostoses and carpal coalition– Tumours; neurovascularTumours; neurovascular

3.3. Duplication:Duplication: thumb,triphalangism/thumb,triphalangism/hyperphalangism, hyperphalangism, polydactyly, polydactyly, mirror handmirror hand

4.4. Overgrowth: limb, macrodactylyOvergrowth: limb, macrodactyly

5.5. UndergrowthUndergrowth

6.6. Congenital constriction band Congenital constriction band syndromesyndrome

7.7. Generalised skeletal abnormalitiesGeneralised skeletal abnormalities

Swanson ClassificationSwanson Classification

Take home messages………Take home messages………

• 10% congenital anomalies occur in 10% congenital anomalies occur in upper limb upper limb

• Embryonic period up to week 8 vital in Embryonic period up to week 8 vital in normal developmentnormal development

• Importance of apical ectodermal ridgeImportance of apical ectodermal ridge

• Homeobox / Sonic hedgehog genesHomeobox / Sonic hedgehog genes

• Swanson classificationSwanson classification

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