Introduction
Someone’s first-ever sip of coffee is often an unpleasant experience that renders them pondering how they could ever learn to like such a foul-flavored drink. Similarly, many health professionals’ first exposure to embryology, and the basic science that is so integral to it, is often a bitter experience. However, over time, dedicated professionals learn how interesting the field is and how essential the knowledge gleamed is pertinent to patient care. This fundamental principle is particularly true for those who choose to enter a field that evaluates and treats newborns with congenital defects.
Congenital anomalies affect somewhere between 1% and 3% of newborns. Among these infants, roughly 1 in 10 has one or more abnormalities that affect their upper extremities. In prevalence, upper-extremity anomalies rank second only to congenital heart defects among malformations present at birth. Most limb anomalies manifest spontaneously or are inherited, with congenital anomalies secondary to teratogens decidedly rare.
For those clinicians that evaluate newborns with hand anomalies as patients, or counsel parents who have already born such a child, a basic understanding of embryogenesis, limb formation, and genetics is utterly essential. Also crucial is understanding how these anomalies may relate to more systemic conditions, as these healthcare providers often are required to counsel parents about the potential effect on future pregnancies and what intervention can and should be done. Understanding genetic criteria and their associated anomalies affords such healthcare providers the capacity to make appropriate recommendations to families and/or referral to clinical geneticist and/or genetic counseling.
The requirements are not the same with all upper-limb congenital anomalies. For example, transverse deficiencies are usually sporadic and carry no appreciable hereditary risk. As such, subsequent pregnancies require no more monitoring than standard care, and there is no need to refer this family to a clinical geneticist. However, concerns about the risks of teratogen exposure elevate when multiple limbs are affected and deficient. This clinical finding suggests some widespread insult to all the developing limb buds and potential teratogen or bleeding abnormality.
Conversely, many other upper-limb anomalies (e.g., radial deficiency) are associated with concomitant, systemic defects ( Fig. 1.1 ). At the same time during embryogenesis when upper-limb anomalies are in their formative stage, other organ systems are developing at the same time. These organ systems can be affected and require evaluation. It is essential that the clinician recognizes those anomalies that typically occur in isolation versus those anomalies that are associated with concomitant anomalies; many of these anomalies may initially be unapparent with dire consequences. This principle is especially crucial when the concomitant anomalies of other organ systems are of greater clinical importance than the limb anomalies. Hand surgeons assessing such patients must focus on the infant’s general health before addressing hand malformations.
Some congenital hand anomalies are linked to other musculoskeletal problems, such as ulnar deficiency. Some anomalies can even be associated with more than one musculoskeletal disorder. For example, central deficiency may be linked to the triad of ectrodactyly ectodermal dysplasia and facial clefts (the so-called EEC syndrome) or lower-limb hemimelia (in which either the tibia or fibula is absent or inadequately formed) ( Fig. 1.2 ).
How Limbs Develop in Utero
Embryogenesis
After an egg is fertilized, the first stage of growth is called embryogenesis. During this period of time, a sequence of events occurs that will determine the number of limbs, their location, and their orientation. In addition, during this time, between the fourth and eighth week of gestation, most upper-extremity congenital anomalies occur. The sequence of events that determines upper-limb development is as follows:
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Day 26 after fertilization: The limb buds initially become visible. The embryo is only about the size of a single grain of rice, roughly 4 mm in length.
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Days 27–47: Over the next 3 weeks, limb buds develop rapidly, but the fingers and toes are not yet identifiable. Even at the end of this period of time, the entire embryo is still only about the size of a lima bean, roughly 20 mm in length.
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Days 48–53: Over the next five or so days, the fingers and toes separate, so that hands and feet become clearly recognizable.
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Day 56: By the end of the eighth week after fertilization, all the essential limb structures are present. Embryogenesis is complete and the next stage of development, the fetal period, has begun.
Fetal Period
Upon the completion of embryogenesis, the fetal period begins. During this stage of development existing structures differentiate, mature, and grow. In the limbs, part of the differentiation and maturation process involves the creation of articulations. Joints form as chondrogen condenses into dense plates between limb structures that will ossify to become bones. Joint cavitation develops the articulation further, though each joint’s development ultimately requires fetal movement to ensure the joint surface is modeled into its final prenatal form.
At a cellular level, limb buds are an outgrowth of mesoderm into overlying ectoderm. Cells from two mesodermal sources—lateral plate mesoderm and somatic mesoderm. These cell lines migrate from their origins into the limb bud. The lateral plate cells eventually become bone, cartilage, and tendon. The somatic cells form muscles, nerves, and vascular elements. Blastemas are clusters of cells that all are destined to differentiate into the same type of tissue. In the fetus’s developing limbs, muscular and chondrogenic blastema, derived from lateral plate mesoderm differentiate into muscles and bones, respectively. The level of oxygen tension appears to play a part in this differentiation process. Chondrogenic blastema is located more centrally within the limb bud where oxygen tension is relatively low. Muscular blastema is more peripheral in location where oxygen tension is greater. Both muscles and the cartilaginous structures that ultimately will ossify to become bones develop sequentially, starting proximal and progressing in a distal direction.
Joints form between the ends of adjacent blastemas, a joint capsule surrounding the interzone and the intervening blastemas cavitating within the interzone’s center to create the articular space. Joint fluid is produced within this space, while cartilage caps the two ends of each bone. Joints ossify and fuse, resulting in synostosis, when the process mentioned earlier fails. Two joints commonly effected by are the proximal radioulnar and ulnohumeral joints ( Fig. 1.3 ). Another component of fetal development that is required for the formation of a functional mobile joint is movement. When fetuses fail to move adequately, as in arthrogryposis, joint spaces become infiltrated by fibrous tissue resulting in contracted and immobile joints ( Fig. 1.4 ).
Signaling Centers
Three growth signaling centers—the apical ectodermal ridge (AER), the zone of polarizing activity (ZPA) and the Wnt (Wingless type)—central to limb patterning align the three spatial axes of limb development. The axes are labeled proximodistal, anteroposterior, and dorsoventral, respectively ( Table 1.1 ). As demonstrated later, our understanding of embryogenesis has been advanced by ingenious experiments performed by embryologists. In these experiments, animal models with limb patterning have been manipulated to permit the dissection and alteration of crucial signaling centers that effect limb development and orientation.
| Signaling Center | Signaling molecule | Limb Axis | Malformation |
|---|---|---|---|
| Apical ectodermal ridge | Fibroblast growth factors | Proximal to distal | Transverse deficiency |
| Zone of polarizing activity | Sonic hedgehog protein | Radioulnar | Mirror hand |
| Wnt pathway | Transcription factor, Lmx-1 | Ventral and dorsal | Abnormal nail and pulp arrangement Nail-patella syndrome |
Proximodistal limb development
Limbs develop in a proximal to distal direction, from shoulder → arm → forearm → hand. The proximodistal signaling center, called the apical ectodermal ridge (AER), is a thickened layer of ectoderm that condenses over each limb bud and secretes proteins that create this effect. Experimental models have been developed to mimic proximodistal limb development. They include removing the AER, which results in limb truncation. Conversely, ectopic implantation of the AER induces the formation of additional limbs. Interestingly, however, removing the AER can be overridden by administering certain fibroblast growth factors that are released by the AER. Moreover, mice deficient in these fibroblast growth factors exhibit complete transverse limb defects.
Given these results, transverse deficiencies are now attributed to deficits in the AER or certain signaling molecules, such as fibroblast growth factors, that it produces ( Fig. 1.5 ).
Anteroposterior limb development
In animal models, both transplantation of the anteroposterior (i.e., radioulnar or preaxial–postaxial) signaling center, called the zone of polarizing activity (ZPA), and transplanting the sonic hedgehog protein that the ZPA secretes have been demonstrated to cause mirror duplication of the ulnar aspect of the limb. Mutant mice with sonic hedgehog protein in their anterior limb bud develop polydactyly. Also in models, triphalangeal thumbs (thumbs with three phalanges, instead of the usual two) have been found to arise secondary to point mutations that generate ectopic sonic hedgehog compound at the anterior margin of the limb bud. In humans, therefore, both mirror hand and certain forms of polydactyly are now attributed to deficits in the ZPA or sonic hedgehog protein ( Fig. 1.6 ).
Dorsoventral limb development
The mechanism behind the development of the dorsum of the finger with its fingernail and the volar surface with its abundant pulp tissue are differentiated and developed is not well understood. The pathway responsible for this differentiation produces one transcription factor, Lmx-1, that induces the mesoderm to adopt dorsal characteristics. In the ventral ectoderm, the Wnt pathway is blocked by a product of a gene called engrailed-1 (En-1). Mice lacking the anteroposterior Wnt signaling pathway, which resides in dorsal ectoderm and secretes Lmx-1, exhibit ventralization of the dorsal surface of their limbs, such that they manifest palmar pads on both sides of their hand: front and back. Conversely, mice lacking the engrailed-1 protein exhibit dorsalization of their limbs’ volar surfaces (so-called bidorsal limbs). Alterations in this latter pathway are relatively rare. Loss of Lmx-1 is associated with a condition called nail-patella syndrome , in which affected individuals have small, poorly developed nails and kneecaps. Affected individuals also have musculoskeletal defects in other areas of the body including their elbows, hips, and chest. Other children may present with anomalies that include extraneous nail or abnormal pulp development, both linked to an altered Wnt signaling pathway. In humans, dorsal dimelia with the nails may present on the palmar surface of fingers, is explained by alterations in the Wnt signaling pathway or Lmx-1 ( Fig. 1.7 ).
