Congenital and Developmental Disorders of the Gastrointestinal Tract

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Chapter 8

Congenital and Developmental Disorders of the Gastrointestinal Tract

Dale Huff

Pierre Russo

Molecular Mechanisms of Gastrointestinal Development

Recent advances in understanding of the molecular controls of gut development have flowed from studies of a number of vertebrate and invertebrate models, including Caenorhabditis elegans, Drosophila, sea urchins, zebrafish, and mice. These studies have provided insights 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, such as the bone morphogenetic protein (BMP), Notch, Homeobox, Hedgehog, and Wnt pathways. A discussion of these studies is beyond the scope of this chapter, and several excellent reviews are available.14 Early development of the endoderm depends on molecular signaling pathways such as that of 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.5 In Drosophila and in the mouse, there are regional differences in the specific expression of Homeobox (Hox) genes along the gut axis.2,4 For example, hindgut defects in mice can be linked to defective expression of Hoxd-13.4

Another family of signaling genes critical in cellular cross-talk is the Hedgehog (Hh) family, which appears to be 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 (EA) to persistent cloaca.6 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.6

Epigenetic factors may also contribute to 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.7 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.4

Embryology and Anatomic Development of the GI 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.2 Major developmental milestones are outlined in Table 8.1. The first two steps take place during the embryonic period, which begins on the day of fertilization and ends on the 56th postconceptual day (week 8). The developing human is more susceptible to teratogenetic 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 and by continued elongation and histogenesis of the GI tract. By 15 to 20 weeks’ gestation, the fetal gut essentially resembles that of the newborn.1 An overview of these basic processes, especially pertaining to the GI tract, is presented in Table 8.2. The pattern of congenital anomalies of the GI tract varies depending on the developmental period from which they arise (Table 8.3).

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.3

Simultaneously, during the third and fourth weeks of development, 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. 8.1). 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 artery, superior mesenteric artery (SMA), and inferior mesenteric artery vascularize the abdominal foregut, midgut, and hindgut, respectively, and by convention determine the boundaries of each (Fig. 8.2).

Organogenesis extends from day 29 to day 56 (weeks 5 through 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 types of fistulas 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 the extrahepatic biliary tree. Dorsal and ventral pancreatic buds also emerge from the proximal duodenum.

It is generally agreed and illustrated in most embryology texts that further development and growth of the gut involves a counterclockwise rotation of 270 degrees during development (Fig. 8.3). However, the exact timing of these events is still subject to disagreement.8 The initial event appears to be herniation of the developing gut into the stalk of the yolk sac during the sixth week, likely because elongation of the midgut proceeds much faster than growth of the embryo and because the concomitant rapid growth of the liver displaces the intestines from the abdominal cavity. As the midgut elongates, it rotates 90 degrees counterclockwise (as viewed from the front of the embryo) around the axis of the SMA, so that the cranial limb (“prearterial” in relation to the SMA) moves to the embryo’s right and the caudal limb (“postarterial”) moves to the embryo’s left (see Fig. 8.3, A and B). Continued elongation, especially of the prearterial segment, results in a series of folds called the jejunoileal loops, the identity of which Keibel believed was retained in the adult.9 The postarterial loop, most of which will form the colon, remains relatively straight. At approximately 10 weeks of life, the intestines return to the abdominal cavity. The factors responsible for this step are unclear, but decrease in the relative growth of the liver and rapid expansion of the abdominal cavity have been suggested. As the gut returns, there is a further anticlockwise, 180-degree rotation, which, added to the previous rotation, makes a total of 270 degrees (see Fig. 8.3, C). Alternatively, some authors have suggested that the gut rotates 180 degrees in the cord followed by a 90-degree rotation during return.8

As a net result of this 270-degree rotation, 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 SMA 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 (see Fig. 8.3, D). 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, and the increasing distance becomes 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 (see Fig. 8.3, E). This separation is referred to, probably incorrectly, as “cecal descent.” See Estrada10 for an extensive review and Kluth and colleagues11 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 histologic 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 lumen 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

Ciliated columnar epithelium covers the epithelial surface of the midesophagus at 10 weeks and spreads to both ends by the 11th week (Fig. 8.4). Stratified squamous epithelium begins to replace the ciliated columnar epithelium in the midesophagus 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, disappearing shortly after birth.1214 Intestinal goblet cells in the distal esophagus have been rarely observed in the neonate and fetus, although positive staining with acidic mucins at the squamocolumnar junction in this age group is common.15 Residual embryonic cells that are induced to proliferate after damage to the squamous epithelium have been postulated to be the source of Barrett metaplasia.16

Pancreatic acinar tissue has been observed in young children at the gastroesophageal junction, independent of Barrett esophagus, esophagitis, or gastritis.17 The superficial cardiac glands of the lamina propria appear during the 13th week. The submucosal mucous glands appear in the 27th week. The circular muscle layer is present at 8 weeks and the longitudinal layer at approximately 13 weeks, followed by the muscularis mucosae.

The waves of differentiation begin in the esophagus, propagating caudally, and at the anorectal junction, propagating cranially; the two meet at the ileocecal junction. Ganglion cells become recognizable by 8 weeks. Their density peaks between 16 and 20 weeks, decreases with increasing gestational age until 30 weeks, then becomes constant.18 The timing of development of the muscle layers and myenteric plexuses in the various segments of the GI tract is outlined in Table 8.4.

Stomach

During the fifth week of life, differential growth of the dorsal wall of the stomach results in 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.19,20

Intestinal villi appear in the cardia and pylorus, where they are normally abundant by 30 weeks (Fig. 8.5). They disappear by birth. Intestinal metaplasia of cardiac or pyloric epithelium may represent a dedifferentiation to the normal fetal condition. The cardiac mucosa is thought to arise from undifferentiated gastric mucosa and not from esophageal metaplasia.21 The development of the gastric glands occurs early during fetal life. Glandular pits are formed during the 11th to 12th weeks of fetal life, along with emergence of the first cells of the parietal lineage. By 15 to 17 weeks of gestation, the fetal gastric glands are essentially similar to an adult’s, with compartmentalization into foveolus, isthmus, neck, and base containing the various phenotypically differentiated cell types.1

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 stomach and which do not produce pepsin in the newborn.22 Gastric pH is relatively high in the neonate; it becomes comparable to that of adults by the age of 2 years. This may result in part from buffering by amniotic fluid but also from a relative lack of gastrin, levels of which increase during the first few postnatal months.22

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.23 Defects in subsequent recanalization of the lumen can result in stenoses or duplications of the digestive tract. As the lumen expands, the epithelium undergoes folding, which will eventually lead to the formation of villi. Mesenchymal cells grow toward the lumen to form early villi, and this process is orchestrated by an elaborate endodermal-mesodermal cross-talk under the control of signaling pathways including the BMP, Hedgehog, platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), and Wnt pathways and the mesenchymal transcription factors FoxL1, FoxF1, and FoxF2.3

Villi and crypts appear first in the duodenum in the 8th week, spread to the middle of the small intestine by the 9th week, and reach the distal ileum by the 12th week. The early intestinal mucosa consists of stratified epithelium; columnar epithelium appears gradually, first at the apices and then along the sides of villi. By the 10th week, only intervillus epithelium remains stratified.2 By 9 to 10 weeks, absorptive cells of the proximal intestine display a brush border with an array of microvilli.24 Eosinophilic globules frequently can be observed within the fetal intestinal epithelium (Fig. 8.6); these have been referred to as “thanatosomes,” and seem to reflect apoptotic activity.25

Both Wnt and BMP signaling pathways appear to be involved in the formation of crypts.3 These crypts contain the stem cells that will serve as the source of the epithelial cells, which are renewed every 4 days.4 Cytologic 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 enteroendocrine cells occurring on top of villi in the duodenum and upper jejunum during the 20th week of gestation have been described as Segi’s cap.26

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 Neurog3.3 Atoh1 (also called Math1) is a basic loop-helix-loop transcription factor that appears to be a key regulator of the development of secretory cells (goblet, Paneth, and enteroendocrine cells), whereas absorptive cells appear to be Math1 independent.27 Neonates have been reported with an absence of gut secretory cells.28 Patients with mutations in a gene called neurogenin 3 (i.e., NEUROG3) have presented with malabsorptive diarrhea and a complete absence of enteroendocrine cells.29 The time of appearance and electronmicroscopic features of 13 enteroendocrine cells have been described in human embryos between 9 and 22 weeks’ gestation.30 Brunner glands appear in the proximal duodenum in the 12th week. The histologic appearance of the small intestine resembles that of a newborn by 20 weeks.31

The enteric nervous system results from 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; the pelvic splanchnic nerves innervate the descending colon and rectum. Postganglionic neurons are derived from neural crest cells, which appear in the fetal gut at approximately 8 weeks’ gestation and migrate in a craniocaudal direction; they may be detected in the rectum by 12 weeks.2 The development of the enteric nervous system is beyond the scope of this chapter, and recent references should be consulted.3236

Similar to the intestinal epithelium, the colonic mucosa consists of a stratified epithelium beginning at about 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. 8.7). 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.22 An outline of the histogenesis of the muscular coats and myenteric plexus is presented in Table 8.4.

The development of the mucosal lymphoid system is outlined in Table 8.5. The fetal mucosal lymphoid system has the capacity to respond to an abnormal intrauterine antigenic stimulus with the formation of germinal centers and plasma cells possibly as early as 20 weeks. 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.

Congenital Anomalies of the GI 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 inherited37 and noninherited maternal and fetal thrombophilic diseases, intrauterine hypoxic/ischemic events, intrauterine infection including varicella,38 iatrogenic vascular disruptions,39 and maternal exposure to vasoactive drugs.40 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.41 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.14 Congenital hiatal hernia, by contrast, appears to develop later in gestation and is caused by defective development of the lumbar part of the diaphragm. The differences between these conditions are of more than academic interest, because the outcome of repair of a congenital short esophagus is more guarded than that of hiatal hernia.41

Esophageal Atresia and Tracheoesophageal Fistula

Atresias and stenoses may occur at any site along the tract, but some sites are more commonly involved than others (Table 8.6). Several disorders associated with multiple atresias or stenoses of the GI tract are listed in Table 8.7. Key distinguishing features of the various types of congenital atresias and stenoses of the GI tract are outlined in Table 8.8. EA with or without tracheoesophageal fistula (TEF) occurs in approximately 1 of every 3000 live births. There is a slight male predominance. A history of polyhydramnios is found in a majority of patients with atresia. EA without a fistula is associated with a small stomach42 and absence of a GI gas pattern. A fistula from the distal esophageal segment allows passage of gastric content into the respiratory tract, causing respiratory symptoms. Approximately 50% of patients have associated congenital anomalies, of which the VATER/VACTERL association (consisting of a combination of vertebral anomalies, anal atresia, cardiac defect, tracheoesophageal fistula, renal and limb anomalies) is the most common.43 Conditions associated with EA and TEF are listed in Table 8.9. Familial forms not associated with hereditary syndromes are probably multifactorial.

Table 8.6

Occurrence of Atresia and Stenosis of the Gastrointestinal Tract

No. Per Live Births* % of All Intestinal Atresia
Esophagus 1 : 3000
Stomach Rare
Duodenum 1 : 1500 50
Jejunum 1 : 2000 20
Ileum 1 : 2000 25
Colon Rare 5
Rectum anus 1 : 5000
Multiple 15

* Number per live births vary widely from series to series.

Data 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.

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Table 8.8

Congenital Atresias and Stenoses of the Gastrointestinal Tract

Location Incidence Key Clinical Features Key Pathologic Features
Esophagus Atresia 1 : 3000
Stenosis 1 : 30,000
>50% associated anomalies; VACTERL association most common
Choking and respiratory distress first day of life
Absence of normal gastrointestinal gas pattern
Stenoses may manifest later in life
Atresias associated with tracheoesophageal fistula in 85% of cases
Stenosis in middle third usually membranous
Stenosis in distal third usually due to tracheobronchial remnant
Stomach 1 : 100,000 Variable; birth to childhood
Prenatal history of polyhydramnios
Nonbilious vomiting; single large gastric bubble
“Single bubble” sign on radiographs in cases of complete obstruction
Some cases may be associated with epidermolysis bullosa, aplasia cutis, or due to pancreatic heterotopias or adenomyoma
Idiopathic hypertrophic pyloric stenosis 1 : 500 Projectile vomiting in first weeks of life
Palpable epigastric mass
Associated with several multiple congenital anomalies syndromes
Concentric hyperplasia and hypertrophy of pyloric muscularis propria
Duodenum 1 : 1500 Most common site of intestinal stenoses
Nonbilious vomiting if proximal to ampulla; bilious if distal
“Double-bubble” gas pattern
Atresias are usually membranous
50% of stenoses are associated with other anomalies, including annular pancreas, or malrotation
Jejunum/ileum 1 : 1500 85% single; 15% multiple
Rare familial forms
Abdominal distention; gas-filled loops
Meconium ileus is presenting feature in 20% of cases of cystic fibrosis
95% are atresias; 5% are stenoses
50% of atresias are type III with associated mesenteric defect
Anorectal 1 : 4000 60% associated with other malformations
Imperforate anus with abnormal perineum
Failure to pass meconium with cutaneous, vesicular, urethral, or vaginal (females) fistulas
High atresias more common in males; low atresias more common in females
Most severe form is persistent cloaca

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CHARGE, Coloboma, heart defect, atresia choanae, retarded growth and development, genital abnormality, and ear abnormality; VACTERL, vertebral anomalies, anal atresia, cardiac defect, tracheoesophageal fistula, renal and limb anomalies)

Data from de Jong EM, Felix JF, de Klein A, Tibboel D. Etiology of esophageal atresia and tracheoesophageal fistula: “mind the gap.” Curr Gastroenterol Rep. 2010;12:215-222.

Gross44 and Swenson and colleagues45 proposed the most commonly used classifications of EA and TEF. Figure 8.8 schematically depicts five common variations found in many current publications. The most common form, comprising approximately 85% of cases, consists of a blind-ending proximal pouch with a fistula from the trachea to the distal portion (Fig. 8.9). The tracheal ostium of a fistula to the distal esophageal segment is often at the carina but may be higher in the trachea. Likewise, the ostium of a fistula to the proximal esophageal pouch is often in the upper trachea but is sometimes lower. The length of the distal segment varies. In some cases, it is a short stump barely visible above the diaphragm, and in some it is subdiaphragmatic.46 The distance between the upper esophageal pouch and the distal esophageal segment may be short or long, depending on these variations. Short gap lesions are more easily and successfully repaired than long gap lesions. A fistula from the upper esophageal pouch or the distal esophageal segment may arise from one or both bronchi forming a bronchoesophageal fistula (or fistulas). The trachea may be absent, in which case the distal trachea or both main bronchi arise from the esophagus. An esophageal stenosis may be present at the site of a TEF without EA.