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Embryology 1 Yen Hsun Chen and Aaron Daluiski Embryology 1 Yen Hsun Chen and Aaron Daluiski Contents Abstract Introduction .......................................... 4 Developmental biology has greatly contributed to the understanding of upper limb develop- Molecular Events of the Developing ment. Whereas early understanding of limb Upper Limb .......................................... 4 development centered on morphological First Phase: Early Development change during organogenesis, current empha- and Limb Identity .................................... 7 sis is on discovery of molecular signaling Second Phase: Limb Patterning mechanisms that drive the remarkable transfor- and Initial Growth ................................... 8 Proximodistal (PD) .................................... 8 mation of single cells into fully functioning Anteroposterior (AP) .................................. 10 limbs and the human body. These discoveries Dorsoventral (DV) ... ................................. 13 have laid a foundation for fundamental Coordination Between Axes .......................... 15 embryology-based concepts that have Third Phase: Tissue Differentiation ................ 19 reshaped the way congenital limb differences Vascular System ....................................... 19 are conceptualized, with the ability to trace a Nervous System ....................................... 19 phenotype back to single genes, and, con- Musculoskeletal System . .. .. .. .. .. .. .. .. .. 20 versely, the ability to predict developmental Extrinsic Factors ..................................... 20 differences from single-gene mutations. Not International Federation of Societies for Surgery only do these discoveries advance understand- of the Hand (IFSSH) Classification System ........ 20 ing of limb development, but clinical benefits Summary ............................................. 21 are also realized. Clinicians are provided with References ............................................ 21 the information they need to adequately inform patients and their families about the nature of limb differences, the hereditary implications, and the downstream developmental needs and challenges that the patient may face. Pediatric upper limb surgeons, standing at the interface between clinical care and genetic research, play a unique role in this field. Through recog- nition of novel human variants, pediatric upper limb surgeons act as gatekeepers by referring patients for appropriate work-up, facilitating Y.H. Chen (*) • A. Daluiski Hospital for Special Surgery, New York, NY, USA research that offers novel insights into human e-mail: [email protected]; [email protected] limb development. The goal of the discussion # Springer Science+Business Media New York 2015 3 J.M. Abzug et al. (eds.), The Pediatric Upper Extremity, DOI 10.1007/978-1-4614-8515-5_1 4 Y.H. Chen and A. Daluiski that follows is to provide the pediatric upper stage than the more distal structures due to earlier limb surgeon with the fundamentals of limb onset of formation. embryology that have implications both clini- A host of genes and molecular signaling work cally and academically. harmoniously together to ensure proper develop- ment of these structures. Much of these mecha- nisms and pathways remain to be worked out, but Introduction there is sufficient knowledge to be able to charac- terize defects in the context of basic embryologi- Congenital birth defects affect 3% of all live births cal events that define the complex, coordinated in the United States, with upper limb differences process of limb development. Whereas early occurring at a rate of approximately 1 per every developmental work focused on the morphology 3,000 live births (Parker et al. 2010). Develop- of these embryological events, the emphasis is ment of the upper limb can be described in terms now placed on understanding the molecular of the anatomic changes that occur during basis of these changes, enabling detailed under- embryonic growth or in terms of the molecular standing of genotype-phenotype correlations that cues that cause the developmental processes. The may have substantial clinical implications. basics of both are important for the upper limb In the discussion that follows, the gene name surgeon to understand to properly evaluate nomenclature will be followed in which human congenital limb anomalies that present clinically. genes are designated by having all letters in upper- It is particularly important to recognize genetic case (e.g., SHH for Sonic Hedgehog) and their defects as they may have wider clinical implica- animal counterparts have only the first letter in tions for the patient. Conversely, the treating uppercase (e.g., Shh). While the two counterparts upper limb surgeon may be the first to identify may be considered interchangeable, this distinc- new clinical presentations that may in turn tion serves as a reminder that not all molecular advance the understanding of embryonic limb mechanisms for limb development may be con- development. served between humans and the mouse, chick, or Normal limb development begins with the other model species. appearance of the upper limb bud as early as postconception day 24 and attains all the major structures of an adult by the end of week 8, the end Molecular Events of the Developing of the embryonic period (O’Rahilly and Gardner Upper Limb 1975). An overview of the milestones of human upper limb development is described in Table 1, Molecular signaling pathways control the growth with select milestones for development of the and tissue differentiation, leading to the gross lower limb for comparison. anatomic milestones of limb development. These The upper limb develops proximal to distal, molecular events can be divided into three phases. starting from the trunk, and begins initially as a The first phase is early limb development, which homogenous mass of undifferentiated mesenchy- includes initial establishment of limb identity and mal cells. During limb outgrowth, musculoskele- the initiation of limb bud outgrowth. The second tal elements generally precede development of phase is generally considered “classical” limb other elements such as nerves, vasculature, and development, characterized by basic patterning lymphatics. Three distinct segments are identifi- of the developing limb. During this phase, limb able in both the developing and mature limb: the patterning is commonly subdivided into three spa- stylopod (upper arm), zeugopod (forearm), and tial axes: proximodistal, anteroposterior autopod (hand plate) (Fig. 1). Development of (radioulnar), and dorsoventral. The third phase is the three segments occurs both sequentially and characterized by growth to increase limb size and concurrently. That is, the most proximal structures cellular differentiation to form discrete tissues that tend to be at a slightly more mature developmental make up the individual structures of the limb. 1 Embryology 5 Table 1 Key milestones in the development of the human upper limb (O’Rahilly and Gardner 1975). Select milestones for the lower limb are provided for comparison. AER apical ectodermal ridge Carnegie Week Day stage Upper limb Lower limb 4 24 11 Swelling appears in region of upper limb bud 28 13 Scattered blood vessels Appearance of lower limb bud 5 32 14 Upper limb AER Early marginal vessel Early brachial plexus development 33 15 Hand plate appears Lower limb AER Humerus mesenchymal condensations 6 37 16 Humerus chondrification Lumbosacral plexus Radius and ulna mesenchymal condensations Brachial plexus with radial, median, and ulnar nerves to the elbow Early muscle masses 41 17 Finger rays (webbed) Femur, tibia, fibula, and tarsus Radius, ulna, and metacarpal chondrification mesenchymal condensations 7 44 18 Interdigital apoptosis Femur, tibia, and fibula chondrification Scapula and humeral head chondrification Carpals and proximal phalanges chondrification Trapezius innervated (accessory nerve) Major muscles distinguishable 48 19 Middle phalanges chondrification Shoulder and elbow interzones (joint cavity formation) 8 51 20 Distal phalanges chondrification 52 21 Humerus ossification Radius ossification All muscles distinguishable Wrist and carpal interzones 54 22 Ulna ossification Femur and tibia ossification 9 57 23 Scapula ossification Fibula ossification Intramembranous ossification of distal tip of Tarsus and digits chondrification distal phalanges These phases are continuous and overlapping. these events produces many of the congenital Early events initiate signaling processes that abnormalities seen clinically. trigger establishment of proper limb patterning. Several key tenets apply: Appropriately patterned groups of cells subse- quently undergo expansion and differentiation to 1. Tissues and structures that develop concurrently form specific limb structures and tissues. While it may be driven by common molecular signaling is more practical to consider each of these pro- pathways, although not always. Defects in com- cesses as distinct steps, these processes overlap in mon pathways may explain constellations of time and space, are dynamic, and are often symptoms that are frequently seen together. interdependent through the cross talk of different 2. Many of the molecular mechanisms identified signaling pathways. Disruption in any number of are derived from experimental work performed 6 Y.H. Chen and A. Daluiski Fig. 1 Anatomy of the developing limb. The development of proximal structures precedes the development of more distal structures due to earlier onset of formation (Zeller et al. 2009) Table 2 Terminology for etiology-based
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