Introduction

In human embryology, weeks 6 through 8 are characterized by the growth and differentiation of tissues into organs. This process is known as organogenesis and occurs from weeks 3 through 8, the embryonic period. During week 3, gastrulation occurs, establishing 3 distinct cell layers: the mesoderm, endoderm, and ectoderm. These are the primary germ cell layers from which organs arise during organogenesis.[1] In particular:

• The endoderm forms the organs of the gastrointestinal and respiratory systems, as well as the thymus, parathyroid, bladder, and urethra.
• The ectoderm is responsible for developing the skin and skin appendages, the nervous system, and portions of sensory organs.
• The mesoderm forms the circulatory system, blood, lymphatic system, bone, cartilage, muscles, and many internal organs. For example, the kidney, spleen, ureters, and adrenal cortex derive from mesoderm.[2]

At the end of week 8, organ systems have developed and are ready for further maturation. By week 9, the fetal period begins, which involves the growth and differentiation of anatomical structures and lasts until birth.

Development

Cardiovascular System

The first organ system to develop during organogenesis is the cardiovascular system. The heart has established its 4 chambers by 4 weeks of development, whereas week 6 involves cardiac outflow separation and descent of the heart (and lungs) into the thorax. The separation divides the truncus arteriosus into the ascending aorta and pulmonary artery; this occurs via spiraling of the aorticopulmonary septum. Anatomically, the aorta and pulmonary appear to wrap around each other superior to the heart. That appearance is the result of embryologic spiraling. The aorticopulmonary septum may also be called the spiral or conotruncal septum.

Lung Development 

Lung development occurs from the embryonic period through the fetal period until birth. In particular, lung growth begins in early embryonic development when right and left lung buds are formed from an initial outpouching, the respiratory diverticulum. The buds enlarge and branch to form the respiratory tree. The appearance of the visceral and parietal pleura takes place during weeks 5 through 7. Both types of pleura arise from mesoderm. The visceral pleura covers the developing bronchial tree, and the parietal pleura covers the internal chest wall. Pleuroperitoneal membranes form and fuse with the diaphragm, which separates the pleural and peritoneal body cavities. Closure of the pleuroperitoneal canal by these membranes takes place by approximately week 7.[3]

Gastrointestinal System

Weeks 6 through 8 are also critical for developing the gastrointestinal system. The midgut undergoes physiologic herniation through the umbilicus around week 6, but this event may be delayed until week 10. This physiologic process happens because the size of the abdominal cavity is too small to accommodate the enlarging gastrointestinal tract. Herniation provides ample space for the rapidly enlarging midgut. After herniation, the midgut undergoes three rotational events totaling 270 degrees of rotation. The first rotation is 90 degrees counterclockwise around the superior mesenteric artery. This helps establish the appropriate arrangement and placement of the bowel; the ileum is brought to the right side of the body. The second rotation occurs during 10 weeks of gestation and consists of 180 degrees in a counterclockwise direction. The midgut returns to the body cavity at the end of 10 weeks. Finally, the third rotation of 180 degrees in a counterclockwise direction places the cecum on the right side.

In early embryonic development, the lumen of the duodenum is occluded by epithelium. Weeks 6 through 8 are important for establishing the lumen's patency as the duodenum expands.[4] The anal opening is established by the breakdown of the cloacal membrane during week 7. The pancreas is endodermal and develops by growing dorsal and ventral pancreatic buds. The buds begin as outgrowths of the duodenum. Week 7 is significant because the dorsal and ventral buds fuse now.[5] The ventral pancreatic bud also undergoes rotation around the duodenum by week 6. It rotates 180 degrees in a clockwise direction.[4] These embryologic mechanisms are important for proper pancreatic development; congenital malformations may occur without such processes, discussed later. Furthermore, the liver undergoes rapid growth during this time. Its first appearance is during the third week of gestation; it undergoes rapid growth during weeks 5 through 10. The hepatic artery appears at week 8. The liver is endodermal in origin.[6]

Central Nervous System

The neural tube closes around week 4 and is the early derivative of the brain and spinal cord. During weeks 5 through 8, the CNS develops its vesicles, embryologic precursors to different brain structures. The forebrain, midbrain, and hindbrain all develop from vesicles. These three structures are the prosencephalon, mesencephalon, and rhombencephalon, respectively. The prosencephalon later develops into the diencephalon and telencephalon. The diencephalon gives rise to the thalami, hypothalamus, optic cups, and neurohypophysis, while the telencephalon grows to surround the diencephalon, midbrain, and hindbrain. The mesencephalon forms the aqueduct of Sylvius, superior and inferior colliculi, and tegmentum. The rhombencephalon gives rise to the fourth ventricle and the metencephalon, a structure that eventually develops into the pons and cerebellum.[7]

Other Organs

Many other organs develop during weeks 6 through 8, including the pituitary gland, thymus, and adrenal cortex. At week 7, the embryo assumes a characteristic C-shape. At week 7, the ocular retina also begins to develop. The upper and lower limbs continue to grow. Also, facial structures such as the nostrils, eyelids, outer ears, lip, and palate develop, and at week 7, the head and face contours begin to emerge.

Cellular

Cellular processes are highly regulated throughout organogenesis. For example, the CNS requires precise cellular pathways for proper organ system development. Part of the dorsal ectoderm becomes the neural ectoderm, whose columnar appearance distinguishes the cells. The neural tube forms during early development and is an embryonic precursor to the CNS. The process by which the neural tube is formed from the neural plate is called neurulation. The neural tube has closed by 4 weeks of development, and the first neurons of the human body begin to appear. The neural tube forms the brain anteriorly, and thespinal cord posteriorly.

During week 7, cells of the ventricular zone of the brain start making neurons of the cortical plate. The ventricular zone is a proliferative cell layer in the brain that surrounds the ventricles and contains neural stem cells for neurogenesis. Neurogenesis describes the formation of new neurons and their incorporation into the CNS. After new neurons are made, they undergo specific pathways of migration and differentiation. These pathways allow for new structures and continued CNS growth and development.[8]

Biochemical

During organogenesis, the fetus is most susceptible to exposure to teratogens. A teratogen is any chemical, infectious agent, or other environmental exposure that can disrupt normal fetal development and lead to congenital abnormalities. For example, the most common teratogen is alcohol exposure in utero, potentially causing fetal alcohol syndrome. This condition can present with growth retardation, neurobehavioral abnormalities, and dysmorphic facial features. Facial abnormalities such as short palpebral fissures, thin upper lip, and smooth philtrum may manifest in the fetus. One contributing biochemical process is the ability of ethanol to cause oxidative stress and produce free radicals. This suppresses oxidative phosphorylation and leads to reduced nicotinamide adenine dinucleotide buildup. Also, it induces apoptosis of neural crest cells, which are critical for forming fetal structures such as the nervous system.[9]

Molecular Level

Many precise molecular events guide normal organ system development. The gastrointestinal system, for instance, arises from the foregut. Hox genes are involved in specific molecular pathways for gut development. Hox gene expression is highly regulated and plays a role in determining the fate of different gut parts. For example, Hoxa3 and Hoxb4 genes have been found in the foregut, while the expression of Hoxc5 occurs in the midgut, and Hoxa13 genes are expressed in the hindgut. This gene expression pattern contributes to the digestive tract's molecular differentiation.[10]

Function

Organogenesis is important for the concurrent development of multiple organs and organ systems. Organs arise from the endoderm, ectoderm, and mesoderm; the three primary germ cell layers are established during gastrulation. Each of these layers is derived from the epiblast. By week 8, organogenesis is complete. The fetus appears human-like and is prepared to undergo further growth and differentiation.

Mechanism

Key embryologic mechanisms are necessary for proper organ development during weeks 6 through 8. Dysfunction during these mechanisms can result in congenital anomalies. The pancreas is one example of an organ that may be disrupted by failed embryologic events. Pancreas divisum is the most common congenital defect involving the pancreas. It occurs due to the failure of fusion of the dorsal and ventral pancreatic buds during the seventh week of gestation. Pancreas divisum causes 2 separate ductal systems to persist rather than 1.

When the dorsal and ventral pancreatic buds fuse, the pancreatic accessory duct may degenerate or become a less functional pancreatic duct. Without fusion of the pancreatic buds, the accessory duct drains most of the pancreas. By contrast, the normal anatomy of the pancreas would cause most drainage through the main pancreatic duct. The majority of patients with pancreas divisum are asymptomatic. However, this anomaly can present in a young child with recurrent episodes of pancreatitis. It should be considered in the differential diagnosis when there are no other known etiologies for pancreatitis in the child.

Another possible congenital malformation of the pancreas is the annular pancreas. The embryologic mechanism by which this occurs is from a failure of rotation of the ventral pancreatic bud. In normal development, the ventral pancreatic bud undergoes rotation with the duodenum. Lack of rotation may cause the ventral pancreatic bud to encircle the duodenum and possibly constrict it. The major complication that may result is small bowel obstruction. Similar to pancreas divisum, many patients with annular pancreas are asymptomatic. Patients who develop symptoms may present with features of a small bowel obstruction, such as bilious vomiting, abdominal pain and distension, and the inability to have a bowel movement.

Testing

The fetal heartbeat may be detected on transvaginal ultrasound beginning around 6 weeks. The presence of a fetal heartbeat helps confirm the viability of a pregnancy. A fetal pole may also be detected at 6 weeks of gestation. The fetal pole is the first sign of the developing fetus that appears on imaging. It can be described as a thickened, hyperechoic structure adjacent to the yolk sac. The fetal pole continues to grow into the developing fetus.

Pathophysiology

As previously stated, cardiac outflow separation occurs around week 6. The truncus arteriosus becomes divided into an ascending aorta and a pulmonary artery via spiraling of the aorticopulmonary septum. Failure of spiraling results in a congenital heart defect known as transposition of the great arteries. In this condition, the ascending aorta and pulmonary trunk are flipped, creating a right-to-left shunt. The aorta arises from the right ventricle, and the pulmonary trunk arises from the left ventricle. As a result, physiologic changes occur in the ventricles. The high pressure of the aorta causes right ventricular hypertrophy. The low pressure of the pulmonary artery causes left ventricular atrophy. This condition is incompatible with life unless a shunt is present, which allows the mixing of oxygenated and deoxygenated blood.[11]

Clinical Significance

Among the most common congenital defects in the United States is cleft lip or palate, which may occur together or separately. A cleft lip occurs when the upper jaw or gum contains an abnormal opening. Clinical presentation varies; the gum may be completely divided in severe cases. However, minor cases may only involve a small notch where the jawbones are separated. Lip formation occurs during weeks 4 through 7. Similarly, cleft palate involves an abnormal opening in the roof of the mouth. It occurs due to the failure of midline fusion of the lateral palatal shelves by week ten. Treatment involves surgical repair.[12]

Omphalocele is a rare birth defect often associated with other congenital anomalies, such as trisomies 13, 18, and 21. Recall that the midgut herniates through the umbilicus during weeks 6 to 7. By week ten, the midgut returns to the abdominal cavity. Failure of the midgut to return to the abdomen results in a congenital malformation known as omphalocele. An omphalocele presents clinically in a neonate with abdominal contents protruding through the umbilicus. They may appear as intestinal loops or involve other abdominal organs like the liver. A thin, transparent sac surrounds the abdominal contents.[13] In contrast, gastroschisis is a birth defect due to a failure of fusion of the lateral folds of the anterior abdominal wall. Gastroschisis also presents at birth, but the abdominal contents protrude through an abdominal wall defect next to the umbilicus rather than through the umbilicus. Also, the protruding abdominal contents are not covered by a sac in gastroschisis.