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Congenital and Developmental Disorders of the Gastrointestinal Tract
Molecular Mechanisms of Gastrointestinal Development
Recent advances in our understanding of the molecular controls of gut development have flowed from studies of a number of vertebrate and invertebrate models, including Caenorhabditis elegans (roundworm), sea urchins, Drosophila, zebrafish, and the mouse. These have provided insight into the genetic mechanisms that direct formation and modeling of the gastrointestinal (GI) tract, highlighted the importance of endodermal-mesenchymal interactions, and demonstrated the high degree of phylogenetic conservation of these mechanisms. Gut development is controlled by a number of intercellular signaling pathways in which transcription factors such as FoxA, GataE, Xlox, Cdx, and Hox11/13b are critical for gut differentiation. A discussion of these studies is beyond the scope of this chapter, and several excellent reviews are available. Early development of the endoderm depends on molecular signaling pathways such as that of the Wnt pathway, which acts by stabilizing β-catenin, allowing it to translocate to the nucleus to activate transcription genes. Ablation of β-catenin in the notochord and primitive streak abrogates endoderm formation. In drosophila and in the mouse, there are regional differences in the specific expression of Homeobox (Hox) genes along the gut axis. , For example, hindgut defects in mice can be linked to defective expression of Hoxd-13. Another family of signaling genes critical in cellular cross-talk is the Hedgehog (Hh) family, which appears essential to anterior-posterior, dorsal-ventral, and radial patterning. Knockout and transgenic mouse models of various hedgehog components result in a variety of malformed phenotypes, ranging from esophageal atresia to persistent cloaca. Vertebrate homologs of Hh exist in three forms: sonic (Shh), Indian (Ihh), and Desert (Dhh), which have different but overlapping expression patterns. For example, Shh – / – mutant embryos die in utero and have overgrown duodenal villi, resulting in occlusion analogous to duodenal stenosis in humans. Selective postnatal blocking of Hh signaling resulted in a wasting and runted phenotype characterized by diarrhea, with disorganized intestinal villi, hyperplastic crypts, and enterocyte vacuolization. Epigenetic factors may also contribute to different phenotypic development as well as disease susceptibility in genetically identical individuals. For example, different degrees of methylation of CpG groups in the agouti mouse, which can vary according to maternal intake of B-group vitamins, may result in variation in coat colors. Epigenetic factors such as diet and the development of the microbiome appear to play a major role, especially in postnatal development of the GI tract.
Embryology and Anatomic Development of the Gastrointestinal Tract
The development of the GI tract proceeds through three major overlapping steps: formation of the gut tube during blastogenesis, differentiation of the specific segments of the digestive tract and its accessory organs during organogenesis, and histogenesis of the individual organs with their specialized cell types. Major developmental milestones are outlined in Table 9.1 . The first two steps, development of the primitive gut tube during blastogenesis followed by organogenesis, take place during the embryonic period, which begins on the day of fertilization and ends on the 56th postconceptual day (8th week). The developing human is more susceptible to teratogenic agents during the embryonic period than at any other period of development. The fetal period, which begins on postconceptual day 57 and ends at birth, is characterized by the final stages of rotation and fixation as well as by continued elongation and histogenesis of the GI tract. By 15 to 20 weeks of gestation, the fetal gut essentially resembles that of the newborn. An overview of these basic processes, especially as pertains to the GI tract, is presented in Table 9.2 . The pattern of congenital anomalies of the GI tract varies depending on the developmental period from which they arise ( Table 9.3 ).
TABLE 9.1
Developmental Milestones
From Montgomery RK, Mulberg AE, Grand RJ. Development of the human gastrointestinal tract: twenty years of progress. Gastroenterology . 1999;116(3):702–731.
| Event | Time of First Expression |
|---|---|
| Gastrulation | Week 3 |
| Gut tube largely closed | Week 4 |
| Liver and pancreas buds | Week 4 |
| Growth of intestines into cord | Week 7 |
| Intestinal villus formation | Week 8 |
| Retraction of intestines into abdominal cavity | Week 10 |
| Organ formation complete | Week 12 |
| Parietal cells detectable, pancreatic islets appear, bile secretion, intestinal enzymes detectable | Week 12 |
| Swallowing detectable | Week 16 and 17 |
| Mature motility | Week 36 |
TABLE 9.2
Overview of Gastrointestinal Development in the First 10 Weeks
| Embryo | Fetus | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Feature | Blastogenesis | Organogenesis | ||||||||
| Week | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 |
| Bilaminar disc, endoderm | X | |||||||||
| Yolk sac, connecting stalk | X | |||||||||
| Trilaminar disc | X | |||||||||
| Early: midline developmental field, induction of gastrointestinal patterning | X | |||||||||
| Late: primitive foregut, midgut, hindgut; respiratory and hepatic primordia | X | |||||||||
| Cylindrical embryo, definitive tubular gastrointestinal tract, umbilical cord | X | |||||||||
| Beginning intestinal rotation | X | |||||||||
| Remodeling, growth, histogenesis; anus completed | X | X | X | X | ||||||
| Return of bowel to abdomen, final rotation and fixation | X | |||||||||
| Sexual differentiation of perineum | X | |||||||||
TABLE 9.3
Patterns of Congenital Anomalies Arising During Various Developmental Periods
From Huff DS. Developmental anatomy and anomalies of the gastrointestinal tract, with involvement in major malformative syndromes. In: Russo P, Ruchelli E, Piccoli D, eds . Pathology of Pediatric Gastrointestinal and Liver Disease . New York: Springer; 2004:3–37.
| Developmental Period | Age (Wk) | Developmental Events | Congenital Anomalies |
|---|---|---|---|
| Embryo | |||
| Early blastogenesis | 1-2 | Basic patterning of body: dorso-ventrality, rostral caudal axis, laterality | Lethal to embryo: empty chorionic sac and global embryonic growth disorganization |
| Late blastogenesis | 3-4 | Midline developmental field Right-left–sidedness (visceral situs) Induction of endodermal primordia Basic patterning of the gastrointestinal tract |
Lethal to embryo: empty chorionic sac and global embryonic growth disorganization Severe gastrointestinal anomalies as part of extensive, sometimes monstrous maldevelopment of embryo, not necessarily lethal (see Table 9.1 ) |
| Organogenesis | 5-8 | Differentiation of endodermal primordia into specific segments of gastrointestinal tract and accessory digestive organ Histogenesis |
Isolated anomalies of the gastrointestinal tract Disruptions and deformations |
| Fetus | |||
| 9-10 | Return and final rotation and fixation of intestinal loop Sexual differentiation of perineum |
Isolated abnormalities of rotation and fixation. Disruptions and deformations. |
|
| 11-34 | Histogenesis, remodeling, growth |
Blastogenesis extends from fertilization to day 28. During the first half of blastogenesis, the bilaminar disc and the basic body plan of dorsoventrality, rostrocaudal axis, and laterality are established. During the second half of blastogenesis, the midline developmental field directs the process of gastrulation, which establishes all three germ layers (endoderm, mesoderm, and ectoderm). The mammalian digestive system is derived from each of these layers: the epithelial lining from the endoderm, the muscle layers and supportive elements from the mesoderm, and the neurons of the enteric nervous system from the ectoderm. It is during this period that the basic plan of the GI tract is established through the inductive influences of the notochord, primitive streak, emerging mesoderm, and other anatomic components of the midline developmental field on the primitive endoderm. These inductive influences predetermine the sites of the specific segments of the GI tract and the primordia of its accessory organs of digestion. For example, at the end of gastrulation in mice, further patterning of the endoderm is determined by regional expression of factors such as Sox2 and Hhex in the anterior endoderm, and Cdx2 in the posterior endoderm. Simultaneously, during the third and fourth weeks, cephalocaudad and lateral folding of the embryo converts the trilaminar germ disc into an elongated cylinder. The primitive gut is at that point somewhat arbitrarily divided into three major segments: a cranial foregut, a midgut open to the yolk sac via the vitelline duct, and a hindgut ( Fig. 9.1 ). Each of these segments will give rise to specialized regions of the gut and, as in the case of the foregut, to other organs such as the thyroid, lungs, liver, and pancreas. The blood supply to the primitive gut is derived from the vitelline arteries of the yolk sac. The celiac, superior mesenteric, and inferior mesenteric arteries vascularize the abdominal foregut, midgut, and hindgut, respectively, and by convention determine the boundaries of each ( Fig. 9.2 ).
Organogenesis extends from day 29 to day 56 (weeks 5 to 8). Suddenly, during the fifth week, the entire tubular GI tract, its major divisions, and its accessory organs of digestion, having been predetermined during blastogenesis, emerge from the imprinted primordium of the primitive endodermal tube. The abdominal portion of the foregut is divided into the esophagus, stomach, and proximal duodenum. The common origin of the trachea and esophagus from the foregut results in various forms of fistulae if separation is incomplete. The hepatic diverticulum arises from the proximal duodenum, its cephalic portion budding into the transverse septum (precursor of the diaphragm) to become the liver, and its caudal portion giving rise to the gallbladder and extrahepatic biliary tree. Dorsal and ventral pancreatic buds also emerge from the proximal duodenum. As elongation of the midgut proceeds much faster than growth of the embryo from the sixth week on, the intestine pushes out into the stalk of the yolk sac. As it does so, it rotates 90 degrees counterclockwise (as viewed from the front of the embryo) around the axis of the superior mesenteric artery (SMA), so that the cranial limb (“pre-arterial” in relation to the SMA) moves to the embryo’s right, and the caudal limb (“postarterial”) moves to the embryo’s left ( Fig. 9.3A,B ). Continued elongation, especially of the pre-arterial segment, results in a series of folds called jejuno-ileal loops, the identity of which Keibel believed were retained in the adult. The postarterial loop, most of which will form the colon, remains relatively straight. Around 63 days of life, under largely unknown influences, the intestines suddenly return to the abdominal cavity. As it returns, there is a further anticlockwise 180-degree rotation, which, added to the previous rotation, makes a total of 270 degrees ( Fig. 9.3C ). As a result, the third portion of the duodenum passes horizontally caudal and dorsal to the artery, and the proximal anchoring point comes to lie near the final position of the ligament of Treitz to the left of the artery. The superior mesenteric artery hangs over the ventral wall of the third portion of the duodenum. As the distal limb then rapidly returns, it swings ventral and rostral to the proximal loop, and the cecum comes to lie in the right abdomen near the liver ( Fig. 9.3D ). Rotation is completed by the 10th week, and fixation continues throughout fetal life as the mesenteries become adherent to the parietal peritoneum. The cecum and liver then separate by unknown mechanisms, the increasing distance occupied by the lengthening ascending colon, with the final position of the liver being the right upper quadrant and that of the cecum being the right lower quadrant ( Fig. 9.3E ). This separation is referred to, probably incorrectly, as cecal descent. See Estrada for an extensive review and Kluth et al. for a recent reevaluation of these events.
Mucosal histogenesis transforms the primitive undifferentiated epithelium of the gut tube into the specific epithelia of the final differentiated segments of the digestive tract. Although histogenesis begins in the late embryonic period, most of the histological transformation occurs during fetal life. It begins with a transient phase of epithelial proliferation. The proliferating epithelium completely occludes the lumen of the duodenum, significantly narrows the lumen of the esophagus, and may mildly narrow the lumens of the cardia, pylorus, upper jejunum, and distal ileum. These proliferations may be accompanied by the transient formation of multiple antimesenteric diverticula in the duodenum, upper jejunum, and distal ileum. Some instances of congenital atresia, stenosis, or diverticula may be the result of abnormalities in the formation or resolution of the proliferative phase.
Esophagus
The esophagus and respiratory apparatus derive from the endoderm and separate from each other during the first month. Ciliated columnar epithelium covers the epithelial surface of the mid-esophagus at 10 weeks and spreads to both ends by the 11th week ( Fig. 9.4 ). Stratified squamous epithelium begins to replace the ciliated columnar epithelium in the mid-esophagus at 16 weeks and spreads proximally and distally to cover the entire esophagus by birth, except for the proximal esophagus, where islands of ciliated columnar epithelium may persist. These disappear shortly after birth. Intestinal goblet cells in the distal esophagus have been rarely observed in the neonate and fetus, though positive staining with acidic mucins at the squamocolumnar junction in this age group is common. Residual embryonic cells that are induced to proliferate after damage to the squamous epithelium have been postulated to be the source of Barrett’s metaplasia. Pancreatic acinar tissue has been observed in young children at the gastro-esophageal junction, independent of Barrett’s esophagus, esophagitis, or gastritis. The superficial cardiac glands of the lamina propria appear in the 13th week. The submucosal mucous glands appear in the 27th week. The circular muscle layer is present at 8 weeks, the longitudinal layer at approximately 13 weeks, followed by the muscularis mucosae. The waves of differentiation begin in the esophagus, propagate caudally, and then propagate cranially at the anorectal junction. The two meet at the ileocecal junction.
Stomach
During the fifth week of life, differential growth of the dorsal wall of the stomach results in the formation of the greater curvature. Subsequent rotation of the stomach 90 degrees along a craniocaudal axis during the seventh week, followed by fixation of the second part of the duodenum to the dorsal body wall forms the lesser sac of the peritoneal cavity. Prenatal ultrasound examinations have shown that the stomach continues to grow in a linear fashion from 13 to 39 weeks. Studies of the development of the mouse stomach have established that epithelial stem cells of the gastric pits reside in the neck region, producing different cell populations that move either upward or downward. , Intestinal villi appear in the cardia and pylorus, where they are normally abundant by 30 weeks ( Fig. 9.5 ). They disappear by birth. Intestinal metaplasia of cardiac or pyloric epithelium may be a de-differentiation to the normal fetal condition. The cardiac mucosa is thought to arise from undifferentiated gastric mucosa and not from esophageal metaplasia. The development of the gastric glands occurs early during fetal life. Glandular pits are formed during the 11th to 12th week of fetal life, along with emergence of the first cells of the parietal lineage. By 15 to 17 weeks of gestation, fetal gastric glands are essentially similar to the adult’s, with compartmentalization into foveolus, isthmus, neck, and base, containing the various phenotypically differentiated cell types. Further development of the stomach involves thickening of the glandular region with proliferation and maturation of the chief cells, which are relatively fewer in the neonatal stomach than in the adult, and which do not produce pepsin in the newborn. Gastric pH is relatively high in the neonate and becomes comparable to that of adults by 2 years of age. This may partly result from buffering by amniotic fluid, but also from a relative lack of gastrin, levels of which increase in the first few postnatal months.
Small and Large Intestine
Rearrangement of the endodermal epithelium resulting from elongation of the gut tube, rather than epithelial proliferation as previously thought, leads to temporary occlusion of the lumen by the end of the sixth week. Defects in subsequent recanalization of the lumen can result in stenoses or duplication of the digestive tract. As the lumen expands, the epithelium undergoes folding that will eventually lead to the formation of villi. Mesenchymal cells grow toward the lumen to form early villi, and this process is orchestrated by elaborate endodermal-mesodermal cross-talk under the control of signaling pathways including the BMP, Hedgehog, PDGF, TGF-β, and Wnt pathways and the mesenchymal transcription factors FoxL1, FoxF1, and FoxF2. Villi and crypts appear first in the duodenum in the eighth week, spread to the mid–small intestine by the 9th week, and reach the distal ileum by the 12th week. The early intestinal mucosa consists of stratified epithelium, with gradual appearance of columnar epithelium, first at the apices and then along the sides of villi. By the 10th week, only intervillus epithelium remains stratified. By 9 to 10 weeks, absorptive cells of the proximal intestine display a brush border with an array of microvilli. Eosinophilic globules can be frequently observed within the fetal intestinal epithelium ( Fig. 9.6 ); these have been referred to as thanatosomes and seem to reflect apoptotic activity. Both Wnt and BMP signaling pathways appear to be involved in the formation of crypts. These crypts contain the stem cells that will serve as the source of the epithelial cells, which are renewed every 4 days. Cytological differentiation of the crypts begins with the appearance of goblet cells in the eighth week followed by Paneth cells and enteroendocrine cells in the ninth week. Clusters of entero-endocrine cells occurring on the top of villi in the duodenum and upper jejunum during the 20th week of gestation have been described as Segi’s cap. The Notch pathway plays a critical role in epithelial differentiation by regulating the specification of absorptive versus secretory lineages, which is controlled by differences in expression of factors such as Hes1, Atoh1 and Neurog3 . Atoh1 (also called Math1 ) is a basic loop-helix-loop transcription factor that appears to be a key regulator of secretory cell (goblet, Paneth, and enteroendocrine cells) development, whereas absorptive cells appear to be Math1- independent. Neonates have been reported with an absence of gut secretory cells. Patients with mutations in a gene called Neurogenin 3 have presented with malabsorptive diarrhea and a complete absence of enteroendocrine cells. The time of appearance and electron-microscopic features of 13 enteroendocrine cells have been described in human embryos between 9 and 22 weeks of gestation. Brunner’s glands appear in the proximal duodenum in the 12th week. The histological appearance of the small intestine resembles that of a newborn by 20 weeks. In addition, perinatal and postnatal acquisition of the gut microbiome is essential for proper maturation and immune development.
The enteric nervous system is derived from the neural crest and includes contributions from the sympathetic system, growing along the arterial supply, and from the parasympathetic system, with branches of the vagal nerve innervating the upper GI tract, while the pelvic splanchnic nerves innervate the descending colon and rectum. The ENS contains > 100 × 10 6 neurons comprising four major classes and at least 18 functional subtypes. These enteric neural crest cells (ENCCs) appear in the developing human foregut around 3 weeks, migrate in a craniocaudal direction, and are detected in the hindgut by week 7. The development of the enteric nervous system is beyond the scope of this chapter, and recent references should be consulted.
Similar to the intestinal epithelium, the colonic mucosa consists of a stratified epithelium beginning around 8 weeks. At approximately the 10th week, villi with developing crypts cover the surface of the large intestine and persist until the 28th week. Therefore intestinal villi are normally seen in the embryo, not only in the small intestine but also in the cardia, pylorus, and colon ( Fig. 9.7 ). The intervillous surface epithelium differentiates into a single layer containing goblet cells by the 13th to 16th week. After birth, a 100-fold increase in the number of intestinal crypts occur, along with an expansion of crypt cells. An outline of the histogenesis of the muscular coats and myenteric plexus is presented in Table 9.4 . The development of the mucosal lymphoid system is outlined in Table 9.5 . The fetal mucosal lymphoid system has the capacity to respond to an abnormal intrauterine antigenic stimulus with expansion of T cells and B cells within Peyer’s patches and the formation of germinal centers and plasma cells, possibly as early as 20 weeks. B cells within patches do not produce IgG until several months postnatally, and the fetus receives its IgG transplacentally from the mother. The neonate responds to the antigenic stimulus of colonization at birth with the formation of germinal centers and plasma cells 2 to 4 weeks after birth.
TABLE 9.4
Histogenesis of the Muscular Coats and Myenteric Plexus
| Small Bowel | Colon | ||||
|---|---|---|---|---|---|
| Layer | Esophagus | Stomach | Distal | Proximal | Distal |
| Circular | 6 | 7 | 7 | 9 | 8 |
| Longitudinal | 8 | 11 | 10 | 26 | 11 |
| Muscularis mucosae | 12 | 14 | 21 | 26 | 21 |
| Myenteric plexus | 6 | 7 | 7 | 8 | 12 |
| Bidirectional peristalsis | 12 | 12 | |||
| Unidirectional peristalsis | 30 | 30 | |||
TABLE 9.5
Histogenesis of Mucosal Lymphoid Tissue
From Huff DS. Developmental anatomy and anomalies of the gastrointestinal tract, with involvement in major malformative syndromes. In: Russo P, Ruchelli E, Piccoli D, eds . Pathology of Pediatric Gastrointestinal and Liver Disease . New York: Springer; 2004:3–37.
| Week | Feature |
|---|---|
| Intrauterine | |
| 7 | Intraepithelial lymphocytes |
| 10 | T cells with surface recognition |
| 12 | PHA-responsive lymphocytes |
| 14 | Lymphocytes with PHA cytotoxicity and ability to mediate graft vs. host response |
| 17-20 | Mast cells in small intestine |
| 19 | Solitary lymphoid follicle in distal ileum, appendix, and colon |
| 24 | Peyer’s patches in distal ileum |
| 40 | Solitary lymphoid follicles in duodenum, rectum, and possibly stomach |
| Postnatal | |
| 2-4 | Germinal centers and plasma cells |
PHA, Phytohemagglutinin.
IgA is the major immunoglobulin of the intestinal mucosa, and though undetectable at birth, it coats the mucosal surface once breastfeeding is initiated and will offer passive immune protection to the infant for several months after birth. Other bioactive compounds in human milk, including oligosaccharides and glycoproteins, also exert protective influences to the developing gut.
Congenital Anomalies of the Gastrointestinal Tract
General Aspects
The causes of anomalies of the GI tract include chromosomal abnormalities (numerical and structural); single-gene defects; maternal diseases, especially diabetes; and maternal exposure to drugs, especially hydantoin (pyloric stenosis, duodenal and anal atresia). Causes of disruptions include inherited and noninherited maternal and fetal thrombophilic diseases, intrauterine hypoxic/ischemic events, intrauterine infection including varicella, iatrogenic vascular disruptions, and maternal exposure to vasoactive drugs. Other diseases of the embryo such as cystic fibrosis and epidermolysis bullosa underlie some GI anomalies. Deformations are limited to abnormal shapes of the liver and abnormal rotation and fixation associated with defects of the diaphragm, body wall, and umbilicus. The cause of most anomalies is unknown. Anomalies that arise after completion of organogenesis are often disruptions or deformations; otherwise the causes are not specific to any developmental period.
Esophagus
Short Esophagus
A congenital short esophagus is a rare anomaly that is associated with intrathoracic development of the stomach. It may be difficult to distinguish from the more common congenital hiatal hernia. Features that favor the diagnosis of a congenital short esophagus include early identification of the intrathoracic stomach during the second trimester and the consistent absence of an abdominal stomach bubble on antenatal ultrasound examination. Furthermore, in the congenital short esophagus, the intrathoracic stomach is supplied by segmental arteries from the descending thoracic aorta, rather than by intrathoracic extensions of the gastric artery, as observed in hiatal hernia. Congenital hiatal hernia, by contrast, appears to develop later in gestation and is a result of defective development of the lumbar part of the diaphragm. The differences between these conditions are more than academic as the outcome of repair of a congenital short esophagus is more guarded than that of hiatal hernia.
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