“ENTODERMAL-ECTODERMAL
ADHESION
SYNDROME’
N. Prop, Ph.D., E. L. Frensdorf, M.D., and F. R. van de Stadt, M.D.
Depart inents of Anatomy/Embryology, Pathology and Surgery, State University of Groningen, Netherlands
FIG. 1. Swelling with healed incision after the first
operation.
(Received July 28; revision accepted for publication October 15, 1966.)
ADDRESS: (NP.) Department of Anatomy and Embryology, State University, Oostersingel 69, Croningen,
The Netherlands.
PEDIATRICS, Vol. 39, No. 4, April 1967
555
S
OME recent papers have paid attention to duplications of the intestine beingas-sociated Witll anomalies in the vertebral column and the spinal cord.’ Various
epit-omizing titles have been proposed for this complex of abnormalities, e.g., combined anterior and posterior spina bifida,5 neuren-teric cysts4’6 or split notochord syndrome. The present paper describes an illustrative case of the syndrome. The embryogenesis of the anomalies will be discussed.
CLINICAL REPORT
Two days after birth, a girl with a gross swelling in the lumbosacral region was ad-milled to the neurosurgical department. The swelling was covered with normal skin. The preoperative diagnosis was meningo-cele. Neurological examination showed
hy-peractive reflexes in combination with a lessened mobility and muscular tone. The four older children of the parents were nor-mal.
An exploratory incision in the swelling
revealed a cavity containing an intestinal
loop. A (myelo-) meningocele was not found. In view of this unforeseen situation, the wound was closed (Fig. 1). An x-ray ex-amination after injection of contrast fluid in the swelling did not show a communication with the coelomic cavity or its intestinum.
After 2% months, a second operation was performed. The surgeon found two
sepa-rate cavities. One sac containing the
intesti-nal loop could be excised completely. There was no evidence of any communication be-tween the sac and the abdominal cavity. The second cavity was membranous and
filled with a clear fluid. The surgeon as-sumed this cavity was a meningocele but it also might be a retention cyst developed after the first operation. After a temporary fistulation the wound was closed. No signs
of increased intracranial pressure appeared. One year after the operation, the mobili-ty of the left leg was subnormal. The left hip joint showed a flexion contraction of 150#{176}.Both feet were in equinus position. In all other respects, the girl was in good health. The abnormalities are to be treated
under care of the revalidation service.
ANATOMICAL AND HISTOLOGICAL
DETAILS OF THE EXCISED MASS
Roentgenography
The most prominent component in the complex of malformed structures was a tu-bular cyst (Fig. 2) possessing a side-tube with a blind end. Both structures possessed a
main
ioop
556 ENTODERMAL CYST
FIG. 2. Excised mass with, at the left side of the figure, the skin with healed
incision and, at the right side, the enteric cyst. The arrow indicates
mesen-teric blood vessels.
lining. \Vell developed blood vessels were present in the mesentery (Fig. 2, arrow). Tile outer layers of both tubes consisted of
peritoneum and two layers of smootil mus-cle. One end of the main loop was connect-ed with subdermal structures (Fig. 3). Its other end was only attached by the mesen-terium. This part of tile lOOfl was lined
in-ternally with gastric mucosa (Fig. 4); as the
subdermal connection was approached, this
epithelium was succeeded by mucosa of the small and, subsequently, large intestinal
skin
cyst
FIG. 3. Scheme of excised skiti, subdermal tissue
niass, and cyst with its blind branch.
type (Fig. 5). The lining cells in the side-tube were large intestinal. Nervous ele-ments were represented by botil intermus-cular and submucosal ganglia.
Figure 6, which is based on an anterio-posterior radiograph, demonstrates that tile
cyst was located dorsal to several cleft lurn-bal and sacral vertebrae. On both sides of the cleft, fused succeeding hemi-vertebrae are found. The morphology of the spinal
cord in the defective area is unknown.
FIG. 6. Scheme of the defective spinal column (kindly supplied by Dr. L. Penning).
Alimentary heterotopia combined with
cleft, wedged, interfused, or displaced ver-tebrae ill the cervical or thoracic parts of the vertebral column have been reported in
some recent papers.”6’ Reports on a
lumbosacral localization of the syndrome are not too frequent. Since 1960, six cases
of the latter type have been described.’4’1’ According to an old theory, complex
mal-formations in general might originate from a dissemination of undifferentiated I3
Experimental evidence shows indeed that isolated embryonic chick cells, when
intro-duced into embryos of the same strain, may develop their own potencies, despite an
alien cellular environment.” However, the complex of structures formed by these dis-seminated cells is quite abnormal and cha-otic, resulting in a teratomatous aggrega-tion of organ rudiments. Such a chaotic mixture of tissue fragments is evidently ab-sent in the complex of anomalies described in this child. Therefore, a genesis from dis-seminated cells for these anomalies seems improbable. The suggestion that the
anoma-FIG. 5. Section demonstrating the presence of large
intestinal mucosa in the cyst (upper part of the figure). The muscular layers in this part of the wall (one arrow) are poorly’ developed. They are
well differentiated in the wall of the adjacent side-tube of the cyst (two arrows; the epithehium of the
side-tube can be seen at the bottom of the picture).
lies migilt be the rudiments of an included twin is not acceptable either.
Combined defects in the dorsomedian area of the body have also been attributed to a fault in the proliferating activity of a “trunk-tail bud” which would form the cellular material for most mesodermal parts of the body.’6 However, the existence of such a biastema, and thus its etiological im-portance, is doubted by modern
embryolo-gists.
The anatomical condition of the spinal cord in the specimina with the syndrome under discussion has been described in two cases only: one possessed a diastemato-myelia,3 the second a diplomyelia.’ In
con-trast, detailed information is available on
as-ectoderm
---neuraL
tube--notochord-
--entoderm- -
-558 ENTODERMAL CYST
‘T1
c‘LJLLGJ
Enteric fistuta Enteric diverticutum Enteric sinus Enteric cyst
FIG. 7. Individuals bearing the syndrome are supposed to have passed through the complex of anomalies
drawn in scheme a.” The open communication with the exterior may be absent. In that case, a diverticulum will reach at the ectodermal layer. The schemes b-e illustrate some possible situations resulting from the
obliteration of various parts of the fistula or diverticulum. The enteric cyst of scheme e represents an
intermediate remnant in a future postvertebral position.
sumed the situation schematized in Figure 7a, showing a fistula between entoderm and ectoderm, while both notochord and neural tube are cleft. Subsequent changes in this triad of anomalies were discussed, apart from Bremer, by Bentley and Smith.3 The
b to e of Figure 7 illustrate some possible situations resulting from an obliteration of various parts of the fistula. A related hy-pothesis has been postulated by Saunders.
The combined occurrence of these anomalies might be due to separate actions of one disturbing factor on different loci in the embryo. It seems simpler to assume that one factor caused a prime anomaly which, in turn, produced defects in other structures. Four hypotheses along this line of thought have been proposed:
cLeft notochord
Bremer’s Theory17”8
A high
hydraulic pressure in the yolk sac of the embryo is supposed to force the for-mation of a dorsal enteric protrusion with, as secondary effects, a cleavage of both no-tochord and medullary plate (Fig. 8a). It may be objected that such a protrusion, if formed, would probably pass by the noto-chord by diverting it.Saunder’s Theory5’7
An unknown factor is supposed to cause a local cleavage of the notochord. This cleft enables entoderm and ectoderm to adhere and to form a “neurenteric band” and an enteric diverticulum (Fig. 8b). With refer-ence to the primary damage supposed, the combined malformations have been named
entoderm
(/[-\\
-cleftmedul-lary plate
#{149} : -cleft
notochord
intestine
(after BREMER)
neural tube
neu renteric
/
#{149}D
bandenteric diverticu(um
(after SAUNDERS)
iiiiii,iiiiiyiiiiii ‘u”-ectoderm
notochord
[
V=.entodermdiverticulum
[forward-invaginati ng
notochordal material
(after BEAROMORE and WIGLESWORTH)
a b
FIG. 8. The schemes illustrate the primary anomaly supposed and its developmental consequences. This anomaly is in (a) a dorsal enteric diverticulum, in (b) a split notochord, and in (c) an ento-ectodermal
O
prochordalplate
I
head process_____of notochord
K
initial position of
HENSEN’s node ‘ /
notochord
I *
I position of
I HENSEN’s
node-after recession
I
_______
primitive________ II streak I
theory is that of Feller and Sternberg.2#{176} Entodermal cells do have a tendency of surface spreading. ‘ This experience might
justify Saunder’s supposition of an entoder-mal expansion through a notochordal cleft. However, students of genetically condi-tioned anterior spina bifida in
never report any anomaly in the gut. A rat embryo which, under the influence of thalid-omide, was completely deprived of lum-bosacral vertebrae24 also seemed normal as to its alimentary tube.
Veeneklaas’ Theory19
During normal development, the noto-chord is intercalated temporarily in the roof
of the primitive gut. According to Veene-kiaas, this intercalation may incidentally re-main as a permanent adhesion between en-toderm and notochord. The adhesion will cause a vertebral dysgenesis by hindering a fusion of left and right halves of the verte-bral primordia. This theory has been ap-plied in a recent paper of Krebs.1’
The value of this concept is limited by the fact that the temporary intercalation of the notochord in the gut wall is normally restricted to the region of the head process and thus to the most cephalad part of tile
notochord. Moreover, the concept fails to explain the origin of postvertebral enteric
tu2
Theory of Beardmore and Wiglesworth1
As a primary event, a local ento-ectoder-mal adhesion would occur in the midline of an embryo at a presomite stage, between Hensen’s node and the prochordal plate (Fig. 8c and 9a). The adhesion will partially block the cephalad invagination of noto-chordal material, causing a splitting or a diverting of the notochord. Because growth implicates that the adhesion will exert a traction force on the wail of the primitive gut, an enteric diverticulum can be
de-veloped. A final result may be the incorpo-ration of intestinal structures in the spinal cord.
K site of entodermal-ectodermat
adhesion
FIG. 9. (a) Original theory of Beardmore and
Wiglesworth. An ento-ectodermal adhesion is sup-posed to be situated between the initial position of Hensen’s node and the prochordal plate. In this site, the adhesion causes a local splitting of the
forward-moving head process. The drawing gives the median structures in a dorsal view. (b) The amended theory. The adhesion is located in the
primitive streak. It causes a temporary splitting of Hensen’s node and, consequently, of the notochord.
The theory only refers to the outgrowth
560
ENTODERMAL CYSTAmendment of the Theory of
Beardmore and Wiglesworth
In human embryos it seems normal that in the region of the primitive streak the outer layer of the germ disc remains sepa-rated from the inner layer.2527 A fusion as
it may have occurred in the two embryos studied by Streeter’8 and by Lewis and Harrison29 seems exceptional but, neverthe-less, possible. A cause for such an ento-ec-todermal adhesion has been suggested by Reinhardt1#{176} (without referring to the paper of Beardmore and Wiglesworth) when dis-cussing the genesis of an enteric cyst in a patient with additional vertebral anomalies. Reinhardt adopted the opinion of many embryologists that the inner cell mass of the human blastocyst becomes split into an ectodermal and an entodermal layer. If a fault in this delamination process would occur, a local adhesion of the two layers could remain. It must be mentioned, how-ever, that the mode of entoderm formation is a matter of controversy. The initial ento-dermal layer (or hypobiast) might also be derived from a source of cells externally of the inner cell mass (see, e.g., Balinsky3#{176} for a discussion of this problem).
Another course of events might be that initially the two layers of the germ disc are normally separated but locally fuse again in a later stage of development. The secon-dary fusion seems possible on the base of a process that has been revealed in the chick.333 A number of entodermal cells is initially located in the surface of the primi-tive streak. From there, they migrate in-ward to join the inner layer of the germ disc. It might be that, incidentally, a minor-ity of these cells prematurely end their mi-gration and form a bridge between the ec-todermal and the entodermal layer in the embryo. Adjoining entodermal and ectoder-mal cells in such a bridge may adhere firmly, as they normally do in both prochor-dal plate and cloacal membrane.
If by one of these causes an ento-ectoder-mal adhesion is formed in the primitive streak, it must be passed by Hensen’s node while this structure is regressing towards
the caudal end of the germ disc. It can be assumed that this passing will cause a tern-porary splitting of the node and, conse-quently, a local cleavage of the notochord at the site of tile adhesion (Fig. 9b). This doubled part in the notochord in turn will induce a local duplication in the neural tube. The adhesion will then be situated in a tunnel formed by clefts in both notochord and neural tube. In a later stage, the tunnel
will offer a passage for the enteric fistula or diverticulum which will be formed if the adhesion succeeds in pulling the gut vail out of its shape.
The theories of Bremer, Saunders, and that of Beardmore and \Viglesworth thus share the opinion that all individuals
bear-ing the syndrome have passed through a
stage with a dorsal enteric fistula (or diver-ticulum) and a cleft in both neural tube and notochord. The latter theory seems most adequate in explaining the origin of these anomalies. A clinical entity of malforma-tions requires an epitomizing name
mdi-eating a key step ill its development, e.g.,
the primary cause or the primary effect. Concerning the syndrome under discussion, we regard a persistent ento-ectodermal adhesion as such a step and, therefore, pro-pose “entodermal-ectodermal adhesion syn-drome” as a title. A sub-title may be ap-plied to indicate the final shape of the dor-sal enteric structure : diverticulum, fistula,
sinus, or cyst.
In the case described here, the dorsal en-teric structure was a tubular cyst in which various types of epithelium had been de-veloped. An exceptional detail, not found in any previous case history, is the duplication of the cyst. Three alternatives are available to explain this phenomenon.
a b C
FIG. 10. A possible transformation of two parallel diverticula in a cyst with a
blind branch.
enteric structure with an occluded lumen which secondarily became duplicated by a
faulty process of vacuolization.
2. Two adjacent ento-ectodermal
adhe-sions could have forced the development of
two parallel diverticula (Fig. 10) which were transformed in a double cyst; asym-metrical growth could have caused a shift of the site of communication.
3. A primarily single diverticulum might have developed a side-tube, like the normal intestine forms a caecai process.
These enteric structures were found in a small, isolated coelomic cavity and were
covered by smooth muscle and peritoneum.
It follows tilat, from both sides, lateral plate material must have moved alongside the enteric protrusion formed. Each lateral plate became normally split into a somatic and a splanchnic layer with a coeiornic cav-ity between. In a later stage, the communi-cation between the abdominal cavity and its postvertebral compartment must have been lost.
SUMMARY
A postvertebral tissue mass excised from the lumbosacral region of a 10-week-old cilild contained a small coelomic cavity and a convoluted enteric cyst with a blind branch. Some cleft vertebrae occurred at the level of tile tissue mass.
The ontogenetic development of this complex of anomalies is explained on the basis of an amended theory of Beardmore
and Wiglesworth. The primary etiological factor is supposed to have been an adhesion among entodermal and ectodermal cells in the median plane of the embryo in a bilam-mar stage. An adhesion of this type can be assumed to cause the following develop-mental disturbances: (1) a dorsal enteric diverticulum (or fistula), (2) a split (or di-verted) notochord and a cleavage of ver-tebrae, (3) a cleft spinal cord. These defects can be modified by growth and processes of repair. With a reference to the primary anomaly produced, “the entodermal-ecto-dermal adhesion syndrome” has been pro-posed as a name for the final complex of malformations.
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Acknowledgment
Thanks are due to prof. dr. A. C. de Wilde
