Pediatric Hand

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Embryology of the Upper Extremity
 EMBRYOGENESIS
Limb development begins during embryogenesis with events
that affect the position and orientation of each limb and the
number of limbs that appear. The limb bud is first visualized
at 26 days after fertilization when the embryo is about 4 mm
in length (crown-rump length), or about the size of a piece of
rice.62,66 The bud rapidly develops through 47 days of life
until the embryo is close to 20 mm in length, or the size of a
lima bean. Fifty-two to 53 days after gestation, the embryo is
22 to 24 mm long and the fingers are entirely separate.30
Eight weeks after fertilization, embryogenesis is complete
and all limb structures are present
 condensation of the chondrogen creates dense plates between future
bones.11 Joint cavitation further forms the articulation, although proper
joint development requires motion for modeling of the ultimate joint
surface. Most upper extremity congenital anomalies occur during this 4-
to 8-week period of rapid and fragile limb development. After 8 weeks’
gestation, the fetal period commences, with differentiation, maturation,
and enlargement of existing structures
 The limb bud represents an outgrowth of the mesoderm into the
overlying ectoderm. Two sources of cells migrate from their origins into
the limb bud.6,11 The cells from the lateral plate mesoderm become
bone, cartilage, and tendon. The cells from the somatic mesoderm form
the muscular, nervous, and vascular elements of the limb bud
 .
 families, the physician must appreciate the signaling centers that
control the three spatial axes of limb development: proximodistal,
anteroposterior, and dorsoventral.11 Each of these limb growth
axes contains a signaling center (i.e., a group of cells) that is
responsible for establishing the corresponding axes; they are the
apical ectodermal ridge (AER), the zone of polarizing activity
(ZPA), and the Wingless type (Wnt) signaling centers (Table
35.2).
 5 A coordinated effort between the AER, ZPA, and Wnt pathways
is necessary for proper limb patterning and axes
development.11,22,36 The three signaling centers are
interdependent, so that the loss of one signal results in
compromise of the entire system.44 There is considerable cross
talk between these signaling pathways during limb development
 development. Programmed cell death is an active process that is genetically
controlled to eliminate unwanted cells during embryogenesis.10 Apoptotic cells
undergo a degeneration process with DNA fragmentation and are eventually
engulfed by phagocytic cells. Genetic control of cell death is necessary during
limb bud formation. For example, the digits initially develop as webbed fingers.
Extraneous tissue between fingers must undergo apoptosis and interdigital
necrosis for finger separation. Failure of interdigital apoptosis results in
syndactyly.65 Interestingly, bone morphogenetic proteins (BMPs), widely
recognized for their role in chondrogenesis and osteogenesis, trigger apoptotic
pathways of the interdigital mesenchyme to produce separated fingers.10 BMP
antagonist can block BMP signaling and prevent apoptosis and interdigital
necrosis. For example, bats have web limbs, and BMP is blocked during their
limb embryogenesis.40 Similarly, altered signaling of fibroblast growth factors,
such as occurs in Apert syndrome, can negate BMP-mediated apoptosis,
resulting in syndactyly (Figure 35.2).
Spatial Axes of Limb Development and
Their Signaling Centers
Proximodistal Limb Development
 The limb develops in a proximal to distal direction, with the
shoulder forming before the elbow and the elbow before the
wrist. This progression is controlled by the AER, a thickened layer
of ectoderm that condenses over the limb bud.11 This signaling
center guides the underlying mesoderm to differentiate into
appropriate structures.6,49 Removal of the AER results in limb
truncation, and ectopic implantation of the AER causes additional
limbs to form (Figures 35.3 and 35.4).11,49,61,66 The secreted
proteins within the AER that yield this effect are fibroblast growth
factors.28,37 In fact, removal of the AER can be overcome by
application of fibroblast growth factors (Figure 35.5). Mice
deficient in various fibroblast growth factors have complete
transverse limb defects.15,38,54
 When explaining this to a parent, we can say that we know
the AER was not physically removed. However, we do have
evidence to suggest that bleeding or ischemia within the AER
resulted in its failure to work properly.17 Transverse
deficiencies are usually sporadic without any underlying
reason. Concern for teratogen exposure is raised when
multiple limbs are involved, suggesting a widespread insult to
all developing limb buds. Transverse differences are not
inheritable, and future children are unlikely to be affected.
Anteroposterior Limb Development
 The limb also develops in an anteroposterior (i.e., radioulnar
or preaxial-postaxial) direction. The ZPA resides within the
posterior margin of the limb bud and functions as a signaling
center for anterior to posterior limb development.6,48 This
signaling pathway polarizes the limb into a radial margin and
an ulnar border.60 The signaling molecule within this
pathway is the sonic hedgehog compound.48 Transplantation
of the ZPA or sonic hedgehog protein causes mirror
duplication of the ulnar
 aspect of the limb (Figure 35.6).11 The extent of duplication is
dose dependent, and greater transference results in more
replication (Figure 35.7).59 This explains the variable numbers of
fingers and different phenotypes of mirror hands (Table 35.3).3
Mutant mice that express sonic hedgehog protein in the anterior
limb bud are polydactylous, with duplication of their ulnar
digits.29 Triphalangeal thumbs arise secondary to point mutations
resulting in ectopic sonic hedgehog compound at the anterior
margin of the limb bud.23
 Sonic hedgehog compound is also expressed in a gradient fashion,
and the duration of exposure of a digit to it determines the
identity of the digit. The anterior digits (index and long fingers)
are exposed for the shortest time, and the small digit is exposed
for the longest time.27,52
Dorsoventral Limb Development
 Dorsoventral limb development, or the process of differentiation
between the dorsum of the finger with a fingernail and the volar surface
abundant with pulp tissue, is not as well understood.11 The Wnt
signaling pathway resides in the dorsal ectoderm and controls this spatial
development. The pathway produces a transcription factor, Lmx-1,
which induces the mesoderm to adopt dorsal characteristics.47 In the
ventral ectoderm, the Wnt pathway is blocked by a product of the gene
Engrailed-1 (En-1). Mice lacking the Wnt pathway have ventralization of
the dorsalsurface (i.e., biventral limbs with palmar pads on both sides of
the foot).20,43 In contrast, mice lacking Engrailed-1 develop
dorsalization of the volar surface (i.e., bidorsal limbs).25 Differences
affecting this pathway are relatively rare. Loss of Lmx-1 is associated
with nail patella syndrome.14 Occasionally, children will present with
anomalies that have an extraneous nail or abnormal pulp development.
These abnormalities are related to the Wnt signaling pathway and occur
sporadically without any definable cause.2
Musculoskeletal System Development
 The muscular blastema and the chondrogenic blastema form the muscles and
bones, respectively.4 The chondrogenic blastema is located in the central
portions,where the oxygen tension is relatively low. The muscular blastema
resides in the periphery, where the oxygen tension is higher. The muscles form
sequentially from proximal to distal, separating from the muscular blastema.
The chondrogenic blastema also forms from proximal to distal, with the
cartilage undergoing ossification to form bones The joints form in interzones
between the ends of two blastemas. A joint capsule surrounds the interzone, and
the intervening blastemas undergo cavitation within the center of the interzone
to produce a joint space. Joint fluid is produced within this space and cartilage
caps the two ends of the bones. Failure of this process results in synostosis
across the intended joint, such as a proximal radioulnar joint or an ulnohumeral
joint (Figure 35.8). Motion is necessary to form a mobile functioning joint. In
the absence of movement, such as arthrogryposis, the joint space is infiltrated
by fibrous tissue, yielding an immobile joint (Figure 35.9).
Genes and Molecular Abnormalities
 The spatial axis of limb development is only one aspect of limb formation. Mutations
encoding signaling proteins, receptor molecules, and transcription factors can alter the
normal limb arrangement and yield anomalies. The number of congenital anomalies seen
by the practicing hand surgeon identifiable at the molecular level increases each year.
Despite the accelerated pace of discovery, only a small number of limb anomalies have
been mapped to specific chromosomal segments and are less defined at the molecular
level.6 Many of these differences, however, are genetically linked with variable patterns
of inheritance. Accurate diagnosis is mandatory, and referral for genetic consultation
warranted. Parents need appropriate counseling regarding the different expressions and
phenotypes across the spectrum of a particular mutation. A continuing misconception is
that an affected parent with a mild phenotype feels that his or her anomaly (heart and/or
hand) is “not so bad and, therefore, my children will be fine like me.” Based on this
misperception, he or she proceeds with pregnancy, naïve to the concept of variable
expression and inconsistent phenotypes. Subsequently, the affected child may be
considerably more affected and the parents are not prepared to handle such involvement.
Appropriate counseling prior to pregnancy can alleviate this misconception and educate
the parents as to the facts surrounding inheritance rates and possible clinical findings.
 The HOX and T-box genes encode transcription factors crucial for limb
formation and exhibit some control over upper limb
formation.6,19,32,35,50,63 Abnormalities in HOX and T-box gene
production alter limb constitution. The extent of malformation is related
to the number and extent of gene irregularities.6,13 HOX genes are
important for the patterning of many tissues in the developing embryo.
Mutations within the HOX gene locus have been identified as the cause
of several types of human differences. Synpolydactyly and hand-foot-
genital syndrome have been related to mutations within the HOX genes
(Figures 35.10 and 35.11).18,31,33,64 Madelung deformity associated
with Leri-Weill dyschondrosteosis has also been connected to HOX
gene defects (Figure 35.12).51 These three entities are autosomal
dominant conditions, although Leri-Weill dyschondrosteosis affects
females more severely. This information is critical to relay to affected
families and justifies genetic counseling.
 The T-box genes are a highly conserved family of transcription factors that
govern both limb and organ system development.1,9 Altered expression of T-
box products can affect the anteroposterior (i.e., radioulnar) development of
the limb. The combination of a cardiac defect and radial deficiency (e.g., Holt-
Oram syndrome) has been specifically linked to the production of transcription
factor Tbx5.7,8,24 Holt-Oram syndrome is an autosomal dominant trait with
variable phenotypes, and affected families would benefit from genetic
counseling. T-box gene mutations have also been linked to limb anomalies
associated with a variety of systemic syndromes, including ulnarmammary
syndrome (Tbx3 mutation),which is associated with postaxial limb
anomalies.5,6,46 The family of BMPs are expressed in the developing limb.11
Cartilage-derived morphogenetic protein appears paramount to digital length
during embryogenesis. Deficiencies in a cartilage-derived morphogenetic
protein are associated with various forms of brachydactyly. Grebe and Hunter-
Thompson chondrodysplasias are associated with severe brachydactyly and have
been directly related to a cartilage-derived morphogenetic protein deficiency
(Figure 35.13).45,58
Systemic Considerations
 During the period of embryogenesis, other organ systems are also developing
and maturing. Errors affecting limb formation can also disturb formation of
these systems. Certain upper limb anomalies are associated with concomitant
systemic disorders (e.g., radial deficiency).12,26 Other limb anomalies occur
in isolation or are combined with other musculoskeletal problems (e.g., ulnar
deficiency).53 Some limb anomalies, such as central deficiency, can be
associated with a systemic condition (EEC syndrome: triad of ectrodactyly,
ectodermal dysplasia, and facial clefting) or can be linked to other
musculoskeletal anomalies, such as lower limb hemimelia. Identifying anomalies
that occur in isolation and anomalies associated with systemic ailments is
mandatory. Many of the systemic illnesses are more important than the limb
anomaly and require accurate evaluation to prevent life-threatening
consequences. The basic molecular events of hand formation are being
discovered at a rapid rate. The complex interaction between signaling centers,
genes, and molecular events complicates direct linkage between an abnormality
and a particular limb
 difference. In addition, variable amounts of gene and
molecular damage result in innumerable different
phenotypes. Application of this basic science knowledge to
the clinical setting is a necessary linkage. The National
Institutes of Health website provides a mechanism for
keeping abreast of current knowledge. Links to the Online
Mendelian Inheritance in Man database offer valuable
information regarding genes and disease. This information is
readily available, frequently updated, and invaluable when
evaluating children with congenital deficiencies.