loop rotates 90° in a counterclockwise direction, so that its position changes from
midsagittal (A) to
transverse (B1). The small intestine forms loops (B2) and slides back into the abdomen (B3) during resolution of the hernia. Meanwhile, the
cecum moves from the left to the right side, which represents the additional 180° counterclockwise rotation of the intestine (C, central view). Omphalocele is caused by
malrotation of the bowels while returning to the abdomen during development. Some cases of omphalocele are believed to be due to an underlying genetic disorder, such as
Edward's syndrome (trisomy 18) or
Patau syndrome (trisomy 13).
Beckwith–Wiedemann syndrome is also associated with omphaloceles.
Pathophysiology Exomphalos is caused by a failure of the
ventral body wall to form and close the naturally occurring
umbilical hernia that occurs during embryonic folding which is a process of
embryogenesis. The normal process of
embryogenesis is that at 2 weeks gestation the human embryo is a flat disc that consists of three layers, the outer
ectoderm and inner
endoderm separated by a middle layer called the
mesoderm. The
ectoderm gives rise to skin and the CNS, the
mesoderm gives rise to muscle and the
endoderm gives rise to organs. The focus areas for exomphalos are that the
ectoderm will form the umbilical ring, the
mesoderm will form the abdominal muscles and the
endoderm will form the gut. After the disc becomes tri-layered, it undergoes growth and folding to transform it from disc to cylinder shaped. The layer of
ectoderm and
mesoderm in the dorsal axis grow ventrally to meet at the midline. Simultaneously, the
cephalic (head) and
caudal (tail) ends of these layers of the disc fold ventrally to meet the lateral folds in the center. The meeting of both axis at the center form the
umbilical ring. Meanwhile, the endoderm migrates to the center of this cylinder. By the fourth week of
gestation the
umbilical ring is formed. During the 6th week the
midgut rapidly grows from the
endoderm which causes a
herniation of the gut through the umbilical ring. The gut rotates as it re-enters the
abdominal cavity which allows for the
small intestine and colon to migrate to their correct anatomical position by the end of the 10th week of development. This process fails to occur normally in cases of exomphalos, resulting in abdominal contents protruding from the umbilical ring. Gut contents fail to return to the abdomen due to a fault in
myogenesis (muscle formation and migration during
embryogenesis). During
embryogenesis the
mesoderm that forms muscle divides into several
somites that migrate dorso-ventrally towards the midline. The somites develop three parts that are
sclerotome which will form bone,
dermatome which will form skin of the back and
myotome which will form muscle. The
somites that remain close to the neural tube at the back of the body have epaxial
myotome, whilst the
somites that migrate to the midline have
hypaxial myotome. The
hypaxial myotome forms the
abdominal muscles. The
myotome cells will give rise to
myoblasts (embryonic
progenitor cells) which will align to form myotubules and then muscle fibers. Consequently, the
myotome will become three muscle sheets that form the layers of abdominal wall muscles. The muscle of concern for exomphalos is the
rectus abdominis. In the disease the muscle undergoes normal differentiation but fails to expand ventro-medially and narrow the
umbilical ring which causes the natural
umbilical hernia that occurs at 6 weeks of gestation to remain external to the body.
Genetics The genes that cause exomphalos are controversial and subject to research. Exomphalos is greatly associated with chromosomal defects and thus these are being explored to pinpoint the genetic cause of the disease. Studies in mice have indicated that mutations in the fibroblast growth factor receptors 1 and 2 (Fgfr1, Fgfr2) cause exomphalos. Mutations in the Insulin like growth factor-2 gene (
IGF2) and its associated receptor gene
IGF2R cause high levels of IGF-2 protein in humans which leads to exomphalos in the associated disease
Beckwith Wiedemann syndrome (BWS).
IFG2R is responsible for degradation of excess IGF-2 protein. BWS disease is caused by a mutation in
chromosome 11 at the locus where the
IGF2 gene resides. Observance of the inheritance patterns of the associated anomalies through pedigrees show that exomphalos can be the result of
autosomal dominant,
autosomal recessive and
X-linked inheritance. Preventive methods that could be utilised by mothers include ingestion of a preconception
multivitamin and supplementation with
folic acid. Termination of pregnancy may be considered if a large exomphalos with associated congenital abnormalities is confirmed during prenatal diagnosis. ==Diagnosis==