Chapter 1
Mechanisms of cleft palate: developmental field analysis

Michael H. Carstens

Saint Louis University and Universidad Nacional Autonoma de Nicaragua, Nicaragua

The purpose of this chapter is to present concepts of cleft palate repair based on a single unifying concept: the embryology of the oronasopharynx. We shall begin with an in-depth discussion of how the bone and soft tissue structures are assembled, based upon the developmental field model. Next, we shall consider how this normal process is altered when a disruption of the neurovascular pedicle to an individual field results in a deficiency state such that the affected field is unable to fuse with its partner fields. Attention will also be give to the effect that such a deficiency state has on the subsequent development of the partner fields. Surgical procedures based on the embryologic model are designed to restore functional tissue relationships.

Craniofacial development: the Lego® model

The anatomic structures of the head and neck are assembled from tissue units known as developmental fields, each of which has a distinct neurovascular pedicle providing sensory and/or autonomic control and blood supply. Fields are often composite structures containing mesenchymal elements such as cartilage, bone, fascia, muscle and so on. They may have an associated epithelium such as skin or mucosa. Adjacent fields interact. Muscles with a primary attachment to bone or cartilage within one field may have a secondary attachment site in an adjacent field.

Fields develop in a strict spatio-temporal sequence. Congenital conditions that reduce the size or content of a field will affect subsequent growth. In the Pierre Robin sequence, the relative decrease in volume of the mandibular ramus leads to a posterior position of the chin and subsequent relationships of the infrahyoid musculature. The reduction of the frontal process of the premaxilla seen in the typical orofacial cleft causes a relative narrowing of the nasal fossa, malposition of the internal nasal valve, and respiratory dysfunction (Figure 1.1).

Figure 1.1 Craniofacial fields are composite blocks of tissue supplied by a specific neurovascular pedicle. Fields grow in relation to each other over time, each with a different volume and rate of growth. Deficiency or absence of a field results in collapse of adjacent partner fields. The leaning tower of Pisa is a classic example of what happens when a supporting field is absent – the entire complex is displaced and, if the upper stories of the tower were made of soft plastic, would become distorted as well. A “cleft” is really a condition of excess or deficiency in a given field that results in displacement and/or distortion of adjacent fields.

The anatomic defects seen in clefts of the hard and soft palate present as a spectrum involving several fields. Many cases involve deficiency states of the piriform fossa and/or premaxilla and soft tissues of the lip and nose. In other, rarer conditions, such as the Tessier 3 cleft, a cleft palate defect coincides with defects in seemingly unrelated anatomic zones, such as the inferior turbinate and medial maxillary wall. For this reason, it is necessary to have a comprehensive picture of the neurovascular anatomy of the oronasopharynx.

The zones of anatomic interest are all supplied by arterial axes running in parallel with the various sensory branches of V1 and V2. Development of the pedicles is a reciprocal process. Neuronal growth cones secrete vascular endothelial growth factor (VEGF) while the arterial growth cone secretes nerve growth factor (NGF). Like all cranial nerves, the trigeminal complex is constructed from neural crest, whereas the histologic composition of the arteries consists of a tubular conduit of endothelial cells made from paraxial mesoderm embraced by pericytes. These latter cells are contractile and control capillary permeability. Pericytes are ubiquitous throughout the human body (Figure 1.2). They are the precursor for mesenchymal stem cells. They also elaborate paracrine factors that are essential for survival of the vascular growth cone. Thus, we come to a very simple and powerful idea: dysfunction of a vascular growth cone will result in either a reduction of volume of mesenchymal structures within the target field, or the outright loss of the field itself. In the first case, the physical effect of the small field is to constrain subsequent growth of surrounding fields. If a frank tissue defect exists (i.e., a cleft) adjacent fields actually collapse into the site.

Figure 1.2 (a, b) Pericytes are ubiquitous throughout the body. They surround all vessels, especially capillaries, providing control of diameter and permeability. Pericytes have contractile fibers. They are interconnected, including between adjacent vessels. Pericytes may have a connection with neural crest, can detach under conditions of inflammation, are the source of white fat, and also give rise to all mesenchymal stem cells of the body. (c) Demonstrated are the multiple physiologic functions of pericytes.

The reader will note here terminology that may be unfamiliar: it harkens back to those embryology lectures that we endured … an endless list of structures that morphed into a final result via mechanisms that were unknown. The molecular revolution transformed the science into developmental biology with a tight connection to genetics (these fields formerly co-existed in virtual isolation from each other). In the following section we shall consider the tissue composition of developmental fields, how they are arranged in the intermediate state as pharyngeal arches, and how, with growth-driven folding of the embryo, these fields become physically repositioned and interactive (Carlson, 2013; Gilbert, 2013).

The embryonic period lasts 8 weeks and is divided into 23 anatomic stages (see Figure 1.3). In the first three stages, the embryo is a rapidly dividing ball of cells. Stages 4–5 are all about survival as the embryo implants itself into the uterine wall and begins the process by which blood supply will come from the mother. The stage 4 embryo secretes fluid into its center, becoming a hollow blastocyst with a single layer of cells, the epiblast, becoming segregated to one side of the ball. Thus there is an inner cell mass (the future organism) and enveloping wall (the trophoblast) that will eventually form the extraembryonic structures, such as the placenta (O'Rahilly & Müller, 1996). The tightly-bound cells of the epiblast then become transiently “loose,” allowing some of the epiblast cells to drop down below their previous plane, coalesce and form a new second layer, the hypoblast. By the end of stage 5, the hypoblast has proliferated and formed a lining layer around the inner wall of the trophoblast. The hypoblast now secretes a new layer, extraembryonic mesoderm (EEM), interposed between it and the trophoblast. This geometry allows the EEM to surround the entire embryo and move into the zone of the future placenta. Since blood vessels are formed exclusively from mesoderm, the EEM becomes the source for the entire extraembryonic blood supply.

Figure 1.3 At stage 5, 9–10 days, the embryo is a hollow ball (blastocyt) consisting of the embryo proper surrounded by trophoblast (green) that will eventually make non-embryonic tissues such as the placenta. From the original inner cell mass a second layer of cells develops beneath. The embryo now has an epiblast (blue), and a hypoblast (yellow), also termed the primitive endoderm. Hypoblast spreads out to line the entire blastocyst cavity. It then secretes the primitive mesoderm (red) which will flow up into the future placenta and make the extra-embryonic circulation.

Stages 6–7 involve a transformation of the intraembryonic tissues into three layers (ectoderm, mesoderm, and endoderm) via a process called gastrulation: “the single most important event in the life of every organism.” There are excellent videos of gastrulation available on YouTube. Note that at the completion of gastrulation, the hypoblast is pushed out of the way; it has no role in the formation of the organism per se. In point of fact, the epiblast contributes first to endoderm, then to mesoderm. When the gastrulation process is complete, the cells remaining behind on the surface are known as the ectoderm proper.

The concept of three germ layers is outmoded and inapplicable to understanding craniofacial development. For simplicity, let's leave the epithelial germ layers (ecto- and endoderm) behind and concentrate on mesoderm. This layer outside the head and neck is responsible for all striated muscles, bone, cartilage, brown fat (white fat is more complex), fascia, and the non-neural internal organs. Furthermore, as mesoderm fans out over the surface of the embryo, its identity becomes determined by the interplay of gene products expressed either from the midline (i.e., the neural tube) such as sonic hedgehog (SHH) and wingless (WNT) or from the peripheral epithelial surfaces of future skin (ectoderm) and mucosa (endoderm) such as BMP-4 (Carstens, 2000, 2002).

Depending upon location, mesoderm assumes three basic fates. Paraxial mesoderm (PAM) lies next to the neural tube. It becomes segmented into individual tissue blocks called somites, each one of which is developmentally related to the segment of the nervous system from which it derives its innervation. Somites construct the entire axial skeleton, related striated muscles, and...