Keywords
OEIS - cloacal exstrophy - limb–body wall complex - body stalk anomaly - pentalogy
of Cantrell - fetal MRI
Fetal ventral body wall defects (VBWDs) comprise a range of congenital malformations
of widely varying severity and prognosis. Some can be isolated and relatively straightforward,
involving high rates of survival to delivery and successful postnatal surgical repair,
such as uncomplicated gastroschisis.[1] Others involve abnormalities of multiple organ systems and have been described as
uniformly fatal, such as limb–body wall complex (LBWC).[2] Several entities previously thought to be unique, such as cloacal exstrophy and
omphalocele, exstrophy, imperforate anus, spina bifida (OEIS) complex, are now regarded
by many as one and the same.[3] Conversely, some conditions initially thought to be represented by a single phenotype,
such as pentalogy of Cantrell (POC), have recently been described as having partial
presentations.[4]
[5] Distinct from uncomplicated omphalocele, which has its own unique developmental
pathophysiology and association with abnormal karyotypes, other types of VBWD involve
some degree of failure of fusion of the lateral and craniocaudal body folds around
the umbilical ring during the 5th and 6th weeks of gestation. While a few sources
have suggested there may be a genetic basis for certain types of these VBWD,[6] the majority indicates that these patients nearly always have a normal karyotype.[7]
[8]
[9]
With improvements in prenatal diagnostic methods, VBWDs are now often detected earlier
in utero. Consequently, an interdisciplinary team of maternal–fetal medicine (MFM)
physicians, neonatologists, pediatric surgeons, pediatric radiologists, and various
other subspecialists can be involved in diagnosis, prognostication, and family counseling.
Aberrations of the fetal ventral body wall can be detected in the late first or early
second trimester, during screening ultrasound (US). At our center, this typically
leads to a referral to MFM and subsequent expert US. Further evaluation with fetal
magnetic resonance imaging (MRI) is performed for cases in which the diagnosis is
in question, lung and/or herniated organ volume measurement are desired, or suspected
neurological anomalies require further characterization.
Diagnosis is often not in question when the VBWD is an isolated defect such as gastroschisis
or bowel-only omphalocele. However, when the defect is more complex, involving the
thorax, pelvis, neural tube, limbs, or genitourinary system, there can be greater
diagnostic difficulty. While there are certainly some published case reports and case
series describing patients whose imaging findings fit neatly within established diagnostic
criteria, many others do not. For these other cases, the findings may straddle multiple
diagnoses or may be best described as “hybrid.” Indeed, many cases initially published
as representative of a certain VBWD were later critiqued in subsequent reports as
having been misclassified. Similarly, multiple retrospective studies that reanalyzed
prenatal imaging found high discrepancy rates between the clinical imaging report
and the diagnosis reached during the study.[7]
[10]
[11]
[12]
[13] This apparent lack of consensus raises questions regarding the benefit of too rigid
and adherence to the traditional diagnostic categories within the range of VBWD. Further,
a review of recent cases encountered within our own prenatal diagnostic clinic confirms
the disparate reports in the literature, and the theme that many patients present
with overlapping features of different VBWD. The practice of prenatal diagnosis depends
on the ability to counsel families appropriately regarding expected outcomes, and
we suggest that the current paradigm is too dependent on rigid diagnostic categories
that do not account for those hybrid cases frequently reported in the literature and
seen in our own cohort.
Materials and Methods
The Institutional Review Board of our academic health care system approved this retrospective
imaging study with waiver of written participant consent.
Literature Review
An extensive review of the literature was performed. First, recent articles pertaining
to the radiologic diagnosis of VBWDs were identified through a PubMed search of “diagnosis”
AND each key phrase: “pentalogy of Cantrell” (155 results), “OEIS” (60 results), “cloacal
exstrophy” (214 results), “limb–body wall complex” (69 results), and “body stalk anomaly”
(BSA) (56 results). These were reviewed and a subset of publications which focused
on prenatal imaging diagnosis was identified and summarized. Further critical review
determined the seminal papers for each diagnosis, from which a narrative of the diagnostic
history of each entity was produced. Next, case reports and case series gathered in
the initial PubMed search of each entity were systematically reviewed to collate diagnostic
criteria, common findings, and reported findings ([Table 1] and [Fig. 1)].
Fig. 1 Overlap of findings for OEIS complex/cloacal exstrophy, limb–body wall complex/body
stalk anomaly, and pentalogy of Cantrell graphically represented. OEIS, omphalocele,
exstrophy, imperforate anus, spina bifida.
Table 1
Reported fetal findings by diagnosis
|
OEIS complex/cloacal exstrophy
|
|
Diagnostic criteria
|
Four key criteria in the acronym
|
|
Omphalocele
|
|
Exstrophy of the bladder
|
|
Imperforate anus
|
|
Spina bifida
|
|
Proposed common findings
|
Kidney malformations (up to 60% of cases[49])
|
|
Hydroureter[49]
[50]
|
|
Hydronephrosis[49]
[50]
[51]
|
|
Congenital megaureter[16]
[52]
|
|
Pelvic kidney[16]
[53]
[54]
|
|
Duplex kidney[16]
[54]
|
|
Renal dysplasia[51]
[55]
|
|
Cystic dysplasia[16]
[49]
[50]
|
|
Renal agenesis[49]
[50]
[52]
[55]
[56]
[57]
|
|
Limb anomalies
|
|
Clubfoot with vertical talus[50]
|
|
Limb length discrepancy[53]
|
|
Bilateral clubfeet[16]
[53]
[56]
|
|
Neural tube defects[57]
[58] (70% of cases[49])
|
|
Spina bifida, myelocystocele[49]
|
|
Terminal myelocystocele[16]
[53]
[54]
|
|
Lumbosacral spina bifida[51]
[56]
|
|
Hindbrain herniation, lipomyelomeningocele[16]
|
|
Omphalocele[16]
[52]
[54]
[55]
[56]
|
|
Spine abnormalities
|
|
Kyphoscoliosis[49]
[50]
|
|
Sacral hemivertebra[55]
|
|
Pubic diastasis[51]
|
|
Missing bladder[16]
[51]
[52]
[53]
[54]
[56]
|
|
Single umbilical artery[16]
[52]
[54]
[55]
|
|
Abnormality of external genitalia[16]
[54]
|
|
Hypospadias[55]
|
|
Bifid corporal bodies[53]
|
|
Duplicated vagina, bifid scrotum, micropenis[56]
|
|
Ambiguous genitalia[51]
|
|
Case reports
|
Intrinsic cardiac abnormalities
|
|
Moderate PDA, small PFO, mild tricuspid regurgitation[54]
|
|
ASD, atrioventricular valve, unroofed coronary sinus, persistent L SVC, LVH[55]
|
|
Single right ventricle[56]
|
|
Pentalogy of Cantrell
|
|
Diagnostic criteria
|
Five distinct criteria, partial cases may have fewer than five
|
|
Intracardiac abnormalities
|
|
Anterior pericardial defects
|
|
Lower sternal defects
|
|
Anterior diaphragmatic defects
|
|
Supraumbilical abdominal wall defects[12]
|
|
Proposed common findings
|
Ectopia cordis[4]
[8]
[22]
[24]
[26]
[59]
|
|
Intrinsic cardiac malformations
|
|
ASD[4]
[26]
[50]
|
|
VSD[4]
[8]
[24]
[50]
|
|
Tetralogy of Fallot[4]
[22]
[24]
[26]
[50]
|
|
Left ventricular diverticulum[26]
[50]
|
|
Transposition of the great vessels[26]
|
|
Tricuspid atresia, dextrocardia, anomalous cardiac venous return[8]
|
|
Neural tube defects[26]
[58]
|
|
Midline supraumbilical abdominal wall defect
|
|
Omphalocele[4]
[8]
[22]
[26]
[50]
[59]
|
|
Diastasis recti abdominis, umbilical hernia, epigastric hernia[50]
|
|
Ventral hernia, open defect[26]
|
|
Supraumbilical hernia[24]
|
|
Sternal defects
|
|
Bifid sternum[4]
[26]
|
|
Cleft sternum[4]
[22]
[24]
|
|
Absence of xiphoid[8]
|
|
Split sternum[26]
|
|
Diaphragmatic defects
|
|
Anterior diaphragmatic hernia[4]
[24]
[26]
[59]
|
|
Pericardial defects
|
|
Pericardial hernia[4]
[50]
|
|
Absent pericardium[26]
[59]
|
|
Umbilical cord defects
|
|
Single umbilical artery[8]
[22]
[60]
|
|
Short cord, hypercoiled cord associated with POC + ectopia cordis[8]
|
|
Facial defects
|
|
Cleft lip and/or palate[26]
|
|
Case reports
|
Aplastic left limb[61]
|
|
Spinal defect[62]
|
|
Hypoplastic lung[26]
|
|
Bronchopulmonary dysplasia, hypoplastic kidney, cleft lip and palate, pulmonary atresia[4]
|
|
Gastroschisis, twin reversed arterial perfusion sequence[8]
|
|
Nonrotation of the midgut, accessory spleen[22]
|
|
Limb–body wall complex
|
|
Diagnostic criteria
|
Two of the following
|
|
Exencephaly or encephalocele with facial clefts
|
|
Thoraco- and/or abdominoschisis
|
|
Limb defects[7]
[63]
|
|
Two distinct phenotypes
|
|
Craniofacial defects often with cranioplacental adhesion and or amniotic bands
|
|
No craniofacial defects but abdominal–placental attachment with short/absent umbilical
cord and urogenital anomalies[35]
|
|
Body stalk anomaly
|
|
Large abdominal wall defect with herniation of abdominal contents into the extraembryonic
coelom
|
|
Absent or rudimentary umbilical cord[34]
|
|
Proposed common findings
|
Absent/rudimentary/short umbilical cord[32]
[34]
[47]
[58]
|
|
Limb anomalies
|
|
Pseudosyndactyly without amniotic bands, oligodactyly, polydactyly, split hand and
foot, single bone forelimb, forebone abnormalities, absent limb and limb girdle, absent
muscles and arthrogryposis[7]
[63]
|
|
Clubbed feet, single lower limb[34]
|
|
Bilateral clubbed feet[32]
|
|
Club foot, rocker bottom foot[47]
|
|
Neural tube defects[46]
[58]
|
|
Exencephaly or encephalocele[7]
[63]
|
|
Abdominal wall defects
|
|
Abdominoschisis[34]
[64]
|
|
Omphalocele[32]
[39]
[47]
|
|
Skeletal abnormalities
|
|
Kyphoscoliosis[32]
[34]
|
|
Scoliosis[46]
[47]
[64]
|
|
Craniofacial abnormalities[28]
[34]
|
|
Case reports
|
Encephalocele, anophthalmia, bilateral cleft lip, thoracic cleft with ectopia cordis,
omphalocele, short umbilical cord, single umbilical artery[39]
|
|
Ectopia cordis[11]
|
|
Anencephaly[32]
|
|
Abdominoschisis, diaphragmatic defect[39]
|
|
Agenesis of the anal canal, agenesis of the genitourinary tract, hypoplastic lungs[64]
|
|
Absent diaphragm, bowel atresia, renal agenesis, anal atresia, no external genitalia[44]
|
|
Anal atresia, no external genitalia, no urinary bladder, hypoplastic lungs[47]
|
Abbreviations: ASD, atrial septal defect; OEIS, omphalocele, exstrophy, imperforate
anus, spina bifida; PDA, patent ductus arteriosus; PFO, patent foramen ovale; SVC,
superior vena cava.
Case Series
The institutional radiology database was queried for MRI of pregnant females over
a 24-month period from January 2016 to January 2018. A total of 364 studies were identified,
24 (6.5%) of which demonstrated findings of VBWD. Cases of isolated omphalocele and
gastroschisis were excluded, leaving a total of 7 out of 24 (29%) studies.
Review of these imaging examinations revealed that MRI was performed for a variety
of clinical indications including concern for fetal pathology, suspected morbidly
adherent placenta, or concern for maternal intra-abdominal inflammatory process.
Maternal clinical and demographic information were obtained from retrospective chart
review, including maternal age, gestational age (GA), parity, race, health conditions,
and medications used during pregnancy. Clinical information about the fetus was obtained
from chart review and included: maternal parity and pertinent medical history, findings
on prenatal US and prenatal MRI, GA at the time of these studies, results of genetic
testing, GA at delivery, delivery history, placenta pathologic examination results,
intrapartum and neonatal outcomes, surgical interventions and intraoperative findings,
mortality, and autopsy results.
US imaging studies were performed via transabdominal technique via GE Voluson 730
(GE Electric Medical System, Milwaukee, WI) with an abdominal convex probe of 3.5
MHz.
MRI studies were obtained from a Siemens 3.0 tesla scanner (MAGNETOM Skyra; Siemens,
Erlangen, Germany). Exact pulse sequences differed depending on the indication for
MRI, but included half-Fourier acquisition single-shot fast spin-echo, balanced steady-state
free precession, T1 spoiled gradient echo, echo planar imaging, and diffusion-weighted
imaging. All scans utilized included three planes of imaging.
Results
Seven cases of prenatal MRI were identified for review. The MRI examinations were
performed between 25 and 37 weeks' GA. For each case, GA at MRI, prenatal imaging
diagnosis, GA at birth, delivery type, Apgar score (when applicable), length of neonatal
hospital stay, type of neonatal surgical repair, surgical diagnosis, pathologic diagnosis,
and ultimate disposition are discussed later.
Case 1
A 35-year-old G4P2012 patient with two prior cesarean sections had a routine prenatal
US at 18 + 4 weeks at an outside hospital showing multiple congenital anomalies including
ventral wall defect. A prenatal MRI was performed at 19 + 4 weeks to further refine
the diagnosis, and expert US was performed at 29 + 2 weeks which showed: (1) a septated
cystic structure at fetal sacrum with no Doppler flow, (2) abdominal wall defect containing
liver, and (3) empty right renal fossa with a right pelvic kidney. MRI examinations
showed: (1) an abdominoschisis containing liver and bowel, (2) pelvic right kidney,
(3) splaying of the bladder into hemimasses, (4) sacral myelocystocele, (5) thoracic
kyphosis (butterfly vertebra), and (6) hypogenesis of the corpus callosum. Calculated
lung volumes were 70% of predicted and invasive placenta previa was noted. Amniocentesis
showed XY with no chromosomal abnormalities and a microarray was normal. Overall,
the findings suggested a diagnosis of OEIS, and the patient was counseled accordingly.
Delivery was at 35 + 5 weeks via cesarean section, and the neonate had a birth weight
of 2,810 g with Apgar scores of 1, 1, and 5 at 1 minute, 5, and 10 minutes, respectively.
There was a three-vessel umbilical cord. Several days after birth, the neonate underwent
surgery to tubularize the colon, form an end colostomy, and reapproximate the bladder
halves. At that time, the patient was noted to have a short colonic segment with two
appendices, giant abdominoschisis, and pelvic findings of OEIS. The patient spent
time admitted to the neonatal intensive care unit (NICU) and had a recovery complicated
by return to the operating room for resection of a bowel stricture. The patient remains
alive.
Case 2
A 29-year-old G3P2 patient with a history of preterm labor had routine prenatal US
showing ventral wall defect, which led to prenatal MRI at 28 + 2 weeks ([Fig. 2]) showing: (1) giant abdominoschisis with fusion of the hernia sac to the placenta,
(2) covered lumbosacral myelomeningocele, (3) unilateral renal agenesis, (4) nonvisualized
bladder with “elephant trunk” appearance of the ileum between hemibladder masses,
(5) narrow thoracic cavity, (6) focal scoliosis with hemivertebra, (7) a shortened
umbilical cord, (8) suspected hypoplastic sternum, (9) small defect in the anterior
left hemidiaphragm and potentially in the diaphragmatic pericardium with inferior
displacement of the heart, (10) complete absence of the right lower extremity, and
(11) hypoplastic left foot and partial amputation of the left tibia. Calculated lung
volumes were 40% of predicted. The patient was referred to our fetal center, and expert
prenatal US at 31 + 1 weeks showed similar findings including: (1) abdominoschisis
with membrane adherent to the placenta, (2) a majority of the abdominal contents herniating
through the defect, (3) absent right lower extremity and hemipelvis, (4) abnormalities
of the distal bones of the left lower extremity, (5) a closed myelomeningocele, and
(6) nonvisualized bladder and genitalia. Cell-free DNA analysis suggested a male fetus
with low risk for aneuploidy. Given the highly complex and varied findings, and especially
given the pulmonary hypoplasia, the patient was counseled that the prognosis was guarded.
Fig. 2 Case 2 sagittal (A, C) and axial (B) SSFSE MRIs. (A, B) No fluid-filled bladder, with “elephant trunk” midline loop of bowel and lateralized
hemibladder masses. (C) Amputated lower limb in patient with myelomeningocele and nonvisualized bladder.
MRI, magnetic resonance imaging; SSFSE, single-shot fast spin-echo.
Delivery was at 33 + 4 weeks via emergent cesarean section at an outside hospital
due to premature labor. The neonate was unable to be adequately ventilated, and died
at 6 hours after birth secondary to extreme metabolic and respiratory acidosis. An
autopsy was not performed.
Case 3
A 32-year-old G2P0101 patient with hypothyroidism and history of preterm premature
rupture of membranes was referred to our center for ventral wall defect, and received
expert prenatal US at 29 + 3 weeks which showed: (1) splayed lower spine with intact
skin, (2) bilateral talipes equinovarus, (3) nonvisualized bladder, and (4) two-vessel
cord. Follow-up prenatal MRI at 31 + 5 weeks showed: (1) infraumbilical abdominoschisis,
(2) nonvisualized bladder with hemibladder masses externally, (3) poorly formed external
genitalia, (4) lumbosacral myelomeningocele, (5) bilateral talipes equinovarus deformity,
and (6) two-vessel cord. The patient did not desire genetic testing. The constellation
of findings was most suggestive of OEIS, and the patient was counseled accordingly.
Delivery was at 35 + 4 weeks via urgent cesarean section for breech position and preterm
labor. The male neonate was transferred to the NICU. At several days of life, the
neonate underwent surgery to form an ostomy and reapproximate the bladder halves.
Repair of the lipomyelomeningocele and tethered cord was conducted months later. Bilateral
pelvic osteotomies with additional iliac closing wedge were done at 13 months of age
and surgery to form an ileovesicostomy was done at 14 months of age. The infant is
currently alive and continues follow-up in the urology and spina bifida clinics.
Case 4
A 28-year-old G2P1001 patient had a routine prenatal US at 18 + 0 weeks which showed:
(1) a ventral wall defect with liver and bowel extrusion, (2) nonvisualized bladder,
(3) possible early ectopia cordis with a structural cardiac abnormality, (4) short
umbilical cord which traveled directly from the anterior placenta to the herniated
organs, (5) motion of fetal extremities but not of the fetal body, (6) scoliosis,
and (7) a right talipes equinovarus deformity. A prenatal MRI at 28 + 5 weeks showed:
(1) nonvisualized bladder with “elephant trunk” appearance of the ileum between hemibladder
masses, (2) infraumbilical abdominoschisis with fusion of the hernia sac to the placenta,
(3) lumbosacral myelomeningocele with scoliosis, (4) a right talipes equinovarus deformity,
(5) narrowed thoracic cavity, and (6) single umbilical artery with a shortened cord
and anomalous fetal insertion (wide separation of the vessels prior to entering the
fetal abdominal cavity). Calculated lung volumes were 25% of predicted. Cell-free
DNA testing suggested a female fetus with low risk for aneuploidy. Given the highly
complex and varied findings, including features of POC, OEIS, and LBWC, and especially
given the pulmonary hypoplasia, the patient was counseled that the prognosis was likely
to be poor.
Delivery was at 32 + 0 weeks via classical cesarean section for preterm labor, with
damage to the ventral hernia sac membrane occurring during delivery, as expected.
At immediate neonatal surgical repair, the patient was found to have a large abdominoschisis
with exstrophy of bladder and a myelomeningocele covered with skin. She was difficult
to ventilate after delivery. A decision for comfort care was made after 6 hours of
life and death occurred shortly thereafter. No autopsy was performed.
Case 5
A 25-year-old G2P1 patient with no significant past medical history had a prenatal
US at an outside center at 19 + 6 weeks which showed an abdominal wall mass and possible
neural tube defect. A prenatal MRI at 22 + 5 weeks showed: (1) an abdominoschisis
containing the liver, (2) two-vessel umbilical cord, (3) nonvisualized urinary bladder
with hemibladder masses, (4) abnormal male external genitalia, (5) lumbar myelomeningocele,
and (6) right renal agenesis. Cell-free DNA testing suggested a male fetus with no
other abnormalities. These features were thought to be most compatible with OEIS,
and the patient was counseled accordingly. However the pregnancy ended with fetal
demise in the second trimester, with delivery at an outside center.
Case 6
A 31-year-old G3P1111 patient had a routine prenatal US at outside center, which showed
VBWD. She presented to our center at 24 + 6 weeks and prenatal MRI was performed ([Fig. 3]), showing: (1) abdominoschisis, (2) myelomeningocele, (3) severe scoliosis, (4)
talipes equinovarus deformity bilaterally, (5) short umbilical cord, and (6) small
thoracic cavity. A second MRI at 28 + 5 weeks redemonstrated the small thoracic cavity.
Calculated lung volumes were 17% of predicted. Karyotype from amniocentesis showed
XY with no other additional studies ordered. Given these findings, the patient was
counseled regarding OEIS as the most likely diagnosis, and given the severe pulmonary
hypoplasia, was told that prognosis was poor. The pregnancy ended with fetal demise
in the third trimester, with delivery at an outside center.
Fig. 3 Case 6 coronal (A) and axial (B) SSFSE MRIs. (A, B) Scoliosis and severely narrowed thoracic cavity, with pulmonary hypoplasia. MRI,
magnetic resonance imaging; SSFSE, single-shot fast spin-echo.
Case 7
A 24-year-old G1P0 patient with sickle cell trait had a ventral defect found on outside
routine prenatal US and underwent prenatal MRI at 21 + 0 weeks which showed: (1) supraumbilical
abdominoschisis, (2) suspected mild defect of the anterior diaphragm and lower sternum/chest
wall, and (3) small thoracic cavity. Calculated lung volumes were 65% of predicted.
An expert prenatal US at 25 + 3 weeks showed: (1) abdominoschisis with liver herniation
and (2) malposition of the cardiac apex abnormally anterior in position. No genetic
testing was desired. At the time of this case study, the fetus is not yet delivered.
Discussion
One of the earliest published reports of cloacal exstrophy was made in the late 19th
century by an Italian teratologist, Dr. C. Taruffi, who also referenced ancient descriptions
of perineal congenital anomalies.[14] In 1978, Carey et al published a case series of 10 patients, the largest to that
date, suggesting the name “OEIS complex,” as a simple and accurate moniker.[11] Importantly, this article proposed that “OEIS complex is a distinct and clinically
recognizable entity of heterogeneous etiology.”[11] Indeed, OEISs represented the consistent findings among the cases, but other malformations,
such as clubfoot and ambiguous genitalia, were also reported. In a 2001 editorial,
Carey clarified OEIS complex and cloacal exstrophy are meant to be synonymous.[3] In 1992, a case report from Smith et al asserted OEIS may be the worst form of the
exstrophy–epispadias sequence but provided no citation for this claim.[6] In 1998, Austin et al proposed a set of diagnostic criteria for US, based heavily
on the initial observations of Carey et al and moving OEIS from a postnatal to a prenatal
diagnosis.[10] They suggested the following major criteria: nonvisualization of the bladder, a
large midline infraumbilical anterior wall defect or cystic anterior wall structure
(persistent cloacal membrane), abdominoschisis, and lumbosacral anomalies, and minor
criteria: lower extremity defects, renal anomalies, ascites, widened pubic arches,
a narrow thorax, hydrocephalus, and a single umbilical artery.[10] In 1999, Hamada et al suggested the midline prolapsed ileum visualized on US between
the hemibladder masses, termed the “elephant trunk sign,” should be added to Austin
et al's sonographic diagnostic criteria.[15] Calvo-Garcia et al reported a case series of eight patients with cloacal exstrophy
suggesting fetal MRI to be useful in the prenatal diagnostic algorithm when US is
inconclusive.[16] They also identified specific fetal MRI findings contributing to the diagnosis of
cloacal exstrophy.[17]
Much of the literature on OEIS is found in urologic journals because these defects
are typically repaired and patients are followed up by pediatric urologists. The oft-quoted
incidence of OEIS, 1 in 200,000 live births originates in a 1970 five case series
with review of cases to date.[18] The incidence of 1 in 400,000 births is from an extrapolation of the rate of bladder
exstrophy and relative proportions of vesical exstrophy complex of anomalies in 1986.[19] These incidences have been questioned in case reports.[13] Recently, a 2011 epidemiologic study from the International Clearinghouse for Birth
Defects Surveillance and Research suggested an overall prevalence of 1 in 131,579
with variance by country.[20] A survival rate of up to 90% was first reported in a series of 34 patients spanning
1963 to 1986 and published in 1987.[21]
POC was first described by Cantrell et al in a 1958 case series of five patients linked
to an additional 16 previously published case reports.[12] In it, they described a syndrome of congenital defects: midline supraumbilical abdominoschisis,
lower sternal defect, deficiency of the anterior diaphragm, deficiency of the diaphragmatic
pericardium, and intracardiac abnormalities. These constitute the five findings necessary
for a diagnosis. Notably, ectopia cordis is not necessary for diagnosis but is often
seen in POC and is considered a poor prognostic factor.[4]
[22] In 1972, Toyama published a case report and review of 60 purported cases of POC,
in which they suggest diagnosing incomplete expression as a variant of the syndrome.[5] Thus, a neonate with partial POC may present with only two, three, or four of the
necessary five defects. In 1998, Vazquez-Jimenez et al conducted an extensive review
of the literature, compiling 153 purported cases of POC and reviewing the spectrum
of malformations.[23] US, the mainstay of prenatal imaging, is most frequently used to assist in the diagnosis
of POC.[22]
[24] Siles et al noted that pericardial effusion was a helpful indicator of a pericardial
defect in a three case series of POC.[25] In 2007, McMahon et al reported the use of combined fetal MRI and fetal echocardiography
to guide prenatal planning.[24] US was considered more useful than MRI for assessing sternal and pericardial defects.
The incidence of POC, which has been quoted at 5.5 in 1 million live births, was first
estimated in a case series of five patients from a population in the Baltimore–Washington,
DC region of the United States.[26] The authors qualified this incidence as a regional estimate. Other descriptions
in the literature suggest estimates ranging from 1 in 6,500 to 1 in 200,000 births.[22] The latter is derived from the 5.5 in 1 million estimate, while the former originates
from a Finnish group who assumed seven cases in 7 years represented the total live
birth incidence of POC in Finland.[27]
LBWC was first reported in the European literature at the start of the 20th century.
Van Allen et al are widely cited as the first to put forward discrete diagnostic criteria
for LBWC in a case series of 25, published in 1987.[7] They based their diagnosis on two of the three following findings: (1) exencephaly
or encephalocele with facial clefts, (2) thoraco- and/or abdominoschisis, and (3)
limb defect. Initially, LBWC was regarding as distinct from a similar diagnosis, BSA.
Embryologically, the “body stalk” is seen early in development, connecting the embryo
to the placenta in early life and is composed of extraembryonic somatic mesoderm and
the three umbilical vessels.[28] Abnormal persistence of this connection has been termed “BSA,” and in a 1992 case
report, Giacoia suggested absence of the umbilical cord and fusion of the organ containing
membranous sac to the placenta as key findings in BSA.[29] Although not clear in the literature as to when, at some point many authors began
to assert that LBWC was equivalent with BSA.[30]
[31]
[32]
[33] Other sources state that these are distinct entities on the same spectrum, and some
have presented criteria on how to differentiate the two. Namely, BSA will not have
extremity defects.[34]
In 1993, based on a review of current literature, Russo et al suggested LBWC presents
with two distinct phenotypes. In this description, the first has two specific findings:
(1) encephalocele or exencephaly, always associated with facial cleft, and (2) amniotic
bands and or broad amniotic adhesion between the cranial defect and the placenta.
The second phenotype will not have the aforementioned findings, but often presents
with (1) urogenital anomalies, (2) anal atresia, (3) lumbosacral meningocele, and
(4) placental abnormalities such as an intact amnion, short cord, and persistence
of the extraembryonic coelom.[35] This nomenclature has been invoked as a valid method to classify LBWC defects by
multiple subsequent authors. US is frequently cited as an effective prenatal diagnostic
modality for this condition,[28]
[30]
[32]
[33]
[34] and Sahinoglu et al put forth sonographic criteria for three phenotypes of LBWC
based on a case series of six.[36] Recently, Aguirre-Pascual et al noted fetal MRI to be useful as an adjunct diagnostic
modality to US in the prenatal characterization of LBWC.[37] LBWC has also been included as one manifestation of the amniotic band sequence,
an idea first proposed by Torpin in 1965.[38]
[39] However, in 1989, a case series of four by Hartwig et al challenged this relationship,
saying that malformations of LBWC are better explained by a malfunction in the ectodermal
placodes.[40] Recently, Moerman et al argued that amniotic band sequence and LBWC represent discrete
entities which have pathogenic overlap as opposed to spectrums of the same disease.[41] Given the large number of cases with normal karyotype, many authors have proposed
a multiple hit phenomenon.[42]
[43] However, in 2011, Hunter et al described an overview of the many diverse theories
and made a case for a primary mechanism.[43] LBWC is considered by most authors to be uniformly fatal with a purported incidence
of 1 in 4,000, though no source is given for this.[44]
The precise pathogenesis of these three entities remains unknown, though frequently
debated. Many theories have been proposed but none has been validated. Many of the
case reports in the literature contain, within a single patient, features from two
or more of these diagnoses or overlapping features from multiple diagnoses. Given
this, some have proposed that these conditions are less likely to be distinct diagnostic
categories with unique pathophysiologic mechanisms, but rather more likely to represent
multiple points along a continuous spectrum. This would also mirror proposals by Smrcek
et al and Hunter et al who each suggested that the numerous manifestations of VBWD
are likely to reflect variations of aberrant cephalic, caudal, and/or lateral folding,
thus giving rise to subsequent patterns of maldevelopment.[30]
[43]
As a clear example, consider the following two sets of criteria which have been asserted
as diagnostic of OEIS and type 2 LBWC ([Table 2]). OEIS is described as omphalocele/exstrophy of the bladder/imperforate anus/spina
bifida, while type 2 LBWC is described as abdominoschisis/urogenital anomalies/anal
atresia/lumbosacral meningocele.
Table 2
Comparison of diagnostic criteria for OEIS complex and type 2 LBWC
|
OEIS complex[11]
|
Type 2 LBWC[35]
|
|
Omphalocele
|
Abdominoschisis
|
|
Exstrophy of the bladder
|
Urogenital anomalies
|
|
Imperforate anus
|
Anal atresia
|
|
Spina bifida
|
Lumbosacral meningocele
|
Abbreviations: LBWC, limb–body wall complex; OEIS, omphalocele, exstrophy, imperforate
anus, spina bifida.
The remarkable similarity of these two sets of criteria confuses the diagnostic process.
Of even greater concern is that the published mortality rates of these two conditions
are incredibly divergent, frequently reported as ∼10% for OEIS, and as 100% for LBWC.[2]
[21] For expectant families, such a wide range of supposed outcomes severely limits the
ability of the perinatal care team to provide proper counseling.
Our case series and review of the literature demonstrate that it can be extremely
challenging to fit a newly diagnosed fetal VBWD into the existing diagnostic categories.
Numerous reported cases of VBWD ([Fig. 4]), rather than fitting completely into one of the traditional diagnostic silos, instead
span across more than one of these diagnoses.[31]
[42]
[45]
[46]
[47]
[48] In our own cohort, six of the seven complicated VBWD cases encountered over a 24-month
period demonstrated just such a hybrid constellation of findings. The traditional
diagnostic categories may obscure more than they reveal.
Fig. 4 Coronal SSFP (A) and sagittal SSFSE (B) MRIs and two transabdominal ultrasound images of several older cases from our center.
(A) Severe scoliosis (black arrow), abdominoschisis (white arrow), and meningocele (short
arrow), but without body wall fusion. (B) Supraumbilical defect (white arrow) and absent bladder. (C) “Elephant trunk” sign representing prolapsed terminal ileum. (D) Fetal fusion to the placenta (white arrow) with large abdominoschisis. MRI, magnetic
resonance imaging; SSFP, steady-state free precession; SSFSE, single-shot fast spin-echo.
We believe that the current paradigm depends too heavily on creating distinctions,
when many cases seem to fall somewhere between two or more of the traditional diagnostic
categories. This is especially clear given the published literature on this topic
is far from uniform agreement. Perhaps most importantly, we need to consider what
approach would be most clinically relevant.
Further, although many of the patients in our cohort exhibited diverse findings related
to multiple diagnoses, six of the seven had findings that correlated well with the
diagnostic criteria for cloacal exstrophy/OEIS. Given the published incidence of around
1 in 200,000 live births, this would mean that six cases in 24 months would represent
a startlingly high rate to a region in the United States which has a total of around
30,000 deliveries annually. An alternative interpretation would be to recognize multiple
of the cases in our cohort as hybrid, and not as completely representative of classic
OEIS.
More importantly, we found that outcomes correlated much more closely with pulmonary
development. In our recent cohort, the prenatal identification of pulmonary hypoplasia
was quite useful, given that our two survivors (cases 1 and 3) had no documented hypoplasia
on prenatal imaging, and three of the four patients who died (cases 2, 4, and 6) had
pulmonary hypoplasia with lung volumes ranging from 17 to 40% of expected.
The size of our patient cohort and the relative infrequency of many of the diagnoses
discussed here is a limitation of this review and analysis. Further, there are inherent
limitations to any analysis of prenatal diagnosis of VBWD given the lack of diagnostic
consensus in the literature, unknown etiology, and absence of confirmatory testing.
Conclusion
Our experience with these complex cases of VBWD reveals that they are most appropriately
understood as existing along a spectrum of anomalies arising from failure of the lateral
and craniocaudal folds to close appropriately early in gestation. Further, our analysis
of the published literature on this topic demonstrates no clear consensus on how to
optimally diagnose those cases which straddle the traditional diagnostic categories
of OEIS/cloacal exstrophy, LBWD/BSA, and POC.
We propose a prenatal diagnostic process that values prognostication and planning
over classification. Key objectives of prenatal diagnosis are to appropriately counsel
families, plan for safe delivery, and direct immediate neonatal management. Any diagnostic
categorization should be at the service of these goals.
At best, a rigid dependence on formal categories can lead to a confusing misnaming
of disease, but at worst, it can result in serious prognostic inaccuracies and lead
to increased distress for families seeking care. As an alternative, we call for the
development of a more descriptive diagnostic approach, depending on type and volume
of organ herniation, degree of pulmonary hypoplasia, and presence of head, body, or
hernia membrane fusion to the placenta. Future prospective studies will be needed
to further elucidate what imaging findings are most predictive of outcome.
