Difference between revisions of "Paper - Studies in the pathology of development 2 (1932)"

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. Streeter, G. L. Focal deficiencies in fetal tissues and their relation to intrauterine amputation. Contrib. Embryol., 1930, 22, 1.
 
  
 
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. Bagg, H. J. Hereditary abnormalities of the limbs, their origin and transmission. II. A morphological study with special reference to the etiology of club-foot, syndactylism, hypodactylism, and congenital amputation in the descendants of X-rayed mice.
 
  
 
==Plates==
 
==Plates==

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Ingalls NW. Studies in the pathology of development: II. Some aspects of defective development in the dorsal midline. (1932) Am J Pathol. 8(5): 525-556 PMID 19970035

Online Editor Note
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  This historic 1932 paper by Ingalls describes early abnormal human development.


This is the first part of his papers: Ingalls NW. Studies in the pathology of development. I. Some developmental risks, the dorsal mid-line. (1932) Quart. Rev. Biol. 7: 48.

Also by this author:



Modern Notes:

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Pages where the terms "Historic" (textbooks, papers, people, recommendations) appear on this site, and sections within pages where this disclaimer appears, indicate that the content and scientific understanding are specific to the time of publication. This means that while some scientific descriptions are still accurate, the terminology and interpretation of the developmental mechanisms reflect the understanding at the time of original publication and those of the preceding periods, these terms, interpretations and recommendations may not reflect our current scientific understanding.     (More? Embryology History | Historic Embryology Papers)

Studies in the Pathology of Development: II. Some Aspects of Defective Development in the Dorsal Midline

N. William Ingalls, M.D. (Frome the Anatomical Laboratory, Western Reserve University, Cleveland, Okio)

Received for publication April 2, 1932.

Introduction

Developmental disorders of various kinds are particularly frequent in the midline of the back. In speaking of the dorsal midline we do not restrict the term to a narrow strip in the axis of the body, but have in mind rather a more extensive area, with variable or even indefinite lateral limits, symmetrically located in respect to the sagittal plane, and extending the entire length of the body, through the head and onto the face. As regards the depth of this region, 3. e., its dorso-ventral extent, it is possible to be rather more precise. It may be considered as extending from the nervous system outward to the covering integument, including both of these as well as all of the varied structures which have their proper place somewhere in between. The deviations from the normal or usual conditions, which may be encountered in this region, range all the way from the most inconspicuous variations and anomalies to wholesale defects of great extent. Hardly noticeable and of no importance at one end of the series, they appear at the other end as gross and widespread malformations, whose presence makes independent existence quite out of the question.

The peculiarities of the dorsal midline, its great inherent sensitivity and the special developmental risks which are attendant upon its proper formation, have been considered more in detail in a recent article,' but a few of the more important points may be noted here again. As a result of the very radical structural alterations, both gross and histological, each with its genetic implications, and of the relatively massive and far-reaching rearrangements of tissues which occur during the formation of the vertebrate nervous system and the restoration of proper continuity over it, there has been impressed upon the whole dorsal midline a certain lability or even a vulnerability, which paves the way for all sorts of defects and variations. The nominal risks incurred in these extensive changes must be further increased by the peculiar qualities and capacities of the cell layers primarily involved — the central nervous system and the epithelial covering of the body. Not only this, but it may very well be that in human development the dangers are even more enhanced, since the necessary developmental procedures must be carried out on tissues whose natural sensitivity has been further increased by specifically human capacities and susceptibilities. Although this applies primarily to the central nervous system, it is not without its effects elsewhere in the midline.

We are concemed at present, however, not with the gross and extensive defects which are so often found on some part of the dorsum, but with the milder, much less serious cases, and with these again in their incipient stages, as they appear in the human embryo relatively early in its development. There can be no doubt that many, if not all of these cases, from the severest to the mildest, belong in the same category, as visible expressions of some derangement in the normal and orderly growth and differentiation of the various structures and tissues concerned. The severest cases are obviously those in which the neural tube is wide open and as a result many other structures are or would have been markedly deficient. It is not so easy to say, on the contrary, what would characterize the mildest cases; or at what point the normal might be said to grade into the abnormal. This difficulty is especially apparent later in development and in the adult, where the multiplicity of the structures involved, their complexity and natural variability, render difficult, if not quite impossible, any very accurate grading as to the severity of the damage done, or as to the extent of deviation from what might be considered essentially normal.

As far as the specimens under consideration at present are concerned, one might have anticipated rather less difficulty in recognizing a varying degree or extent of injury to the embryo, but conditions are by no means so evident or uncomplicated. Leaving the nervous system out of account, the structure of the body wall dorsal to it is still, in these cases, exceedingly simple and the opportunities for deviations from the normal would appear to be rather limited. But even here, however, during the first two months of development there is not a little variety in the degree and character of the tissue changes in the midline. These vary considerably in location, extent and apparent severity, as well as in the histological pictures presented. For these reasons it is not often possible to distinguish between earlier or later stages of the same process, if such there be; nor can one always be sure that the real damage to the tissues is greater or more serious in one case than in another. It is altogether probable that the slightest degrees of disturbed development do not appear in this series at all. They would be expected in apparently normal embryos, but only further development would reveal the presence and extent of such latent defects. As long as growth and differentiation might continue there would be the opportunity for these weak or submerged influences to manifest their own peculiar character. In the present series, however, only those cases have been included which show definite and undoubted alterations in the embryo, readily discernible on gross examination.

On account of the importance and significance of the central nervous system in the formation and inherent integrity of the dorsum, and on account of the simplicity of the dorsal structures in the earlier stages, it is convenient to classify the various malformations in this region in terms of the condition of the nervous system. In most of the cases to be considered here, and in all of the more typical ones, the nervous system has been properly formed and closed in behind, while the defects which occur involve only the dorsal body wall, connective tissue and covering epithelium. Since these disturbances in development are much less marked and since they appear only after the neural tube has closed, they may be looked upon as relatively mild derangements. It is not implied, however, that the formation and closure of the neural tube guarantees in any way its own subsequent normal development, any more than that the same would hold for the overlying structures. In these typical, milder cases, the nervous system is to all appearances normal and intact, but the overlying parts give unmistakable evidence of being the site of abnormal processes. What continued development would have brought about may be very problematical, but the visible evidences of the damage already done are confined to the parts dorsal to the nervous system, or even to the superficial epithelium.

One cannot escape the conclusion that in the formation of the central nervous system and of the various structures which close it in dorsally, a very definite developmental risk has been incurred, and that the parts concerned have had impressed upon them a greater degree of sensitivity and vulnerability than is to be found elsewhere. In the great majority of cases development proceeds normally throughout the body, but disturbed or altered environmental conditions may be expected to compromise or upset, more or less seriously, this orderly development, exactly at those points where the cells and tissues are, for some reason, the most sensitive. There are, early in the life history, particularly in man, two especially vulnerable regions of the body: one is the dorsal midline, the other is the distal portion of the extremities. In view of the normal and inherent susceptibility of these parts to unfavorable environmental influences, it is not necessary to predicate any special germinal, genetic defect to account for most of these cases of maldevelopment. It would seem very probable, however, that this same susceptibility might be a favorable or vulnerable point of attack for various influences which would later appear as germinal or hereditary defects. In any case, the ultimate factors involved are essentially germinal, whether they merely determine an unusual, even dangerous sensitivity, or whether they actually allow or lead to gross malformations. If the genetic composition of the future individual prescribes and carries through a certain normal course of development, then it also and just as certainly provides many of the pitfalls along the way.

The individual specimens to be described below have been arranged roughly in order of the degree of disturbance in the dorsal midline, with some regard also for the general condition and quality of the embryo, beginning with those which show the most pronounced defects and terminating with those where the damage done is relatively slight and perhaps of no very great consequence. The purpose of this arrangement is to call attention to, and to contrast with each other, the major and minor defects which occur in this region. On the one hand the developmental disturbance is at a maximum, with extensive involvement of the nervous system; while on the other it is at a minimum, and only slight alterations in the superficial epithelium can be made out. Between these extremes the order is less trustworthy and of less significance, as already indicated.


Description of Specimens

The first few specimens which will be considered have been included here simply as illustrations of typical, major midline defects in the embryo. They stand at one end of the series, which at the other fades out into normal or quasinormal conditions. The series presented here might have been extended, a greater variety of cases might have been introduced and the descriptions and histories could have been more detailed, but we have endeavored to cover the more important points in a reasonable amount of space.

Embryo No. 83

Fig. 1. Embryo No. 83.

(Fig. 1). No history was available. The embryo is rather pale and chalky in appearance and there is a deep tear ventrally between head and trunk, which exposes the heart. Before being damaged the greatest length would have been approximately 7mm. The head is rather small and there is little relief or detail to be made out. The cord is small and shows no trace of vessels.

Beginning about the first sacral segment and extending almost to the end of tail, there is a wide-open defect in the neural tube. This defect is perfectly regular in outline, measures 2.5 mm. in length and occupies the prominent convexity of the sacral curve extending over eight to ten segments. It is widest near its anterior limit, a little less than 1 mm., while at the opposite end it is a trifle more than o.5 mm. in width. There is a distinct, sharp linear groove in the center, which does not quite reach the anterior limit of the defect, due to the rolling in here to form the neural tube. At the caudal end the median groove appears to run out onto the dorsum of the tail, and there is no evidence of any attempt at closure or even of the presence of nervous system beyond this point. The widely everted walls of the neural tube, on either side of the midline, are smooth and convex, no details being visible. Their lateral margins are sharp and even and overhang slightly the adjacent body wall.

Sections of the embryo show that extensive disintegrative changes are well underway. These are most noticeable in the head where the brain has suffered most. In some parts of the nervous system, more especially in the cord, the ventral portions seem rather better preserved and less affected than the dorsal parts, but this might be an indication of better nutritive or circulatory conditions in the former. In spite of the fact that the open neural tube in the sacral region was sharply defined and seemed very well preserved in the gross specimen, the changes in its walls are more marked than in any other part of the embryo. The form has been preserved but the substance is almost lacking. There has been an extensive cytolysis and the remaining tissue is more like an attenuated mesenchyme than nervous or epithelial tissue. The free, exposed surface is often irregular and indefinite, while the deeper surface seems to merge in many places into the loose underlying mesenchyme.

The vesicle which contained this embryo was rather large, 29 by 27 by 22mm., the villi were well developed and numerous, but many of them showed early cystic changes. Within the sac there was a large amount of dense, stringy magma which quite obscured the embryo. The amnion was of normal size but much thickened, and presented a large rent through which the embryo had escaped. Except for a few fine tortuous vessels faintly visible on the yolk-sac, there were no vascular channels to be seen anywhere.

Embryo No. 46

Fig. 2. Embryo No. 46.

(Fig. 2). There was a cessation of menstruation in this case two and a half months before the abortion, but the embryo is much younger than this, for its maximum length is only 14.5mm. It is markedly stunted and malformed, of a brownish, muddy color, more opaque than normal and has obviously been dead for some time. The body is short and straight, rather cylindrical and gives the impression of being unduly distended. The head is extremely defective, most of the brain seems to be absent, so that the face sets on the anterior part of the trunk with the upper margin of the mouth as the most prominent point. The limbs are fairly well developed although the posterior ones are somewhat retarded. The cord is short and much constricted at its embryonic and chorionic attachments. Between these points it is very greatly dilated, with no evidence of vessels within.

Occupying most of the dorsum of the body and extending forward to within 1 mm. of the eyes is a large pyriform area over which the superficial ectoderm is either lacking or markedly altered. This area is quite symmetrical and measures 9 mm. in length by 6 mm. in width. It is widest in front where it is also raised a little above the general body surface, its limits are quite sharp and even, and it is distinguished from the rest of the embryo by a slight yellowish tinge. In its anterior part this surface is dull and uneven, marked by small, shallow, irregular furrows and depressions or even small cavities. The picture presented is that of a disintegrating surface tissue, the end results of which are seen in the posterior part of the area. In this later location there is a deep, rather clean defect which was originally filled with prominent, but very irregular masses of degenerating nervous tissue. This tissue was so friable and loosely attached that it was lost in the removal of the embryo from the sac.

Except for the nervous system the body tissues and organs are in better condition than was anticipated. The anterior end of the nervous system shows the characteristic complicated foldings and widespread histolysis and both the pigment and nervous layers of the retina show similar changes. Farther back, as shown in the gross specimen, practically all of the brain and cord has been lost. A study of the sections reveals the fact that the superficial ectoderm is still present over much of the anterior part of the dorsal area which appeared defective upon gross examination. The superficial layers are, as a rule, somewhat thickened, but there are various places where they are quite thin or even entirely wanting. Structurally there is little to be made out definitely, but this region stands in marked contrast with the smooth, even development of the surface epithelium in other parts of the body. It is obvious that the proper development of the ectoderm of the dorsum of the embryo has been radically altered. The original disturbance, whatever it may have been, has not prevented the closure of the neural tube, at least in its anterior part. It has, nevertheless, left its impress on the superficial layers which make up the skin in this region, as shown by its abnormal appearance, both in the gross and microscopic. This compromising of the proper development of the superficial structures in the midline of the back, with little or no involvement of the central nervous system, will be brought out more in detail in the later cases. It is the expression of a greater sensitivity or vulnerability in this region, due primarily to the massive and radical developmental processes which form the central nervous system and the body wall behind it.

The chorionic vesicle is very large, 60 by 40 mm., thin-walled, and shows extensive hemorrhagic areas; most of its surface is covered by thin, adherent decidua and it is filled with a turbid, blood-tinged fluid. The amnion is everywhere in contact with the chorion, but no vessels are to be seen, even in the immediate neighborhood of the embryo. Villi are few in number, small and fibrous.

Embryo No. 129

Fig. 3. Embryo No. 129.

(Fig. 3). The embryo is represented by a fairly regular, cylindrical mass with rounded ends, 12 mm. in length by 6 mm. in diameter. It is the most stunted and deformed of any of the embryos in this series and shows in addition some of the most interesting surface changes. The color in general is a grayish brown with some darker blotches, while the cord, which comes off the ventral surface at the posterior end of the body, is much lighter. The face, and what remains of the head, make up the anterior hemispherical end of the embryo, the only relief here being found by the wide-open, quadrangular mouth which is completely filled by the tongue. The eyes on both sides show a well defined ring of retinal pigment, with the choroidal fissure pointing toward the mouth.

On the dorsum of the embryo, but much nearer the anterior end, there is a roughly circular, well defined area, which measures about 4-5 mm. in diameter. In spite of the brownish cast and general discoloration of the embryo, this patch, on what should be the vertex or back part of the head, stands out very conspicuously. It is quite symmetrical but a trifle more extensive on the left side along its posterior border. Within this area a little differentiation can be made out, in that the central portion is smoother and rather yellowish in color, while outside of this is a darker, uneven, ragged zone covered over with numerous small appendages or tags of tissue. There is nothing to indicate an open neural tube in this region, the appearance being rather indicative of profound alterations in the superficial tissues.

The sections show that the embryo is much older and more advanced than its gross characters might indicate. The brain and head in general are very defective. The cartilaginous skeleton of the vertebral column and of the larger bones of the extremities is very well defined, but there is a very marked kyphosis, the anterior end of the spine being at right angles to the more posterior portions. The superficial tissues of this embryo, especially in the dorsal area noted above, present a most bizarre and unusual appearance. No attempt will be made at this time to describe in detail these conditions which appear quite foreign and out of place in an embryo of this stage of development. While much of the superficial ectoderm, and in varying extent the underlying tissue also, are very radically altered, the greatest degree of histological distortion and maldevelopment is found in the circumscribed area on the back. There is here an extensive but very irregular thickening of the surface layers, and also what may be called provisionally a widespread hyperkeratosis, with a varying amount of desquamation and the formation of structures which may be characterized as epithelial pearls. The connective tissue beneath is often thick and dense and there are large spaces or clefts, but their relation to epithelium or connective tissue is not always clear. In a few scattered areas there are very definite pigment cells, usually occurring in small clumps. One of the most remarkable features in this specimen is the contrast presented in different tissues in regard to their preservation and in the evidences of continued cell life and activity. Although practically all of the embryo shows advanced histolysis and general disintegration, with the exception of the cartilaginous elements, there are certain regions on the dorsum where the subepithelial structures appear to be made up of perfectly normal healthy cells. It is here that one encounters a rather dense connective tissue, with groups of cells of doubtful significance which often contain conspicuous masses of pigment. The staining quality of the tissues in these regions is quite satisfactory, while everywhere else it is very poor if not entirely wanting. Although the embryo as a whole and almost all of its constituent cells have long since been dead, the cells in the areas just noted seem to have been living practically up to the time of fixation. They form an oasis, as it were, in the desert of death and dissolution around them. They are also peculiar in that they seem to represent a stage in development much in advance of the possible chronological age of the embryo. In this precocity, if the term is permissible, there may be some pathological tendencies, and the same would apply to the hyperkeratosis, so-called, in the overlying ectoderm. The general picture is that of a histological differentiation far in advance of what it should be, a remarkable form of prosoplasia.

The chorionic vesicle is very large, quite out of proportion to the embryo, measuring about 60 by 100 mm. It is invested everywhere by a thick layer of clotted blood. Its internal surface is rough, uneven and dark in color, due to the extensive clots without. The amnion and chorion are fused. The villi are not very numerous, they are thick and fibrous and there is considerable leucocytic infiltration in the surrounding blood. No vascular connections between embryo and chorion are visible.

Embryo No. 665

This specimen is from a first pregnancy at the age of 17 years. There is a history of pernicious vomiting. The menstrual history is somewhat uncertain, but the last period was at least two months before abortion. On account of the damage to the posterior end of the body, the original length cannot be determined, but it was probably not far from 15 mm. The head is small and the details of the face much obscured. Over the anterior end of the head and the upper part of the surface ectoderm is lacking. This defective area is rather extensive and quite symmetrical; it is bounded by a line which runs from about the angle of the mouth upward and backward across the eyes, reaching the midline behind, not far from or just beyond the midbrain. The surface of this area is rather more brownish in color and along its margins the adjacent body epithelium appears loose and slightly elevated. In the midline behind the large superficial defect, in what seems to be the region of the lower rhombencephalon, there is a small, elongated, deep-seated, apparently hemorrhagic spot about 0.5 mm. in length.

Although the ventral thoracic and abdominal walls are torn away, exposing the heart, there are some evidences that the anterior body wall might have been defective over the upper part of the heart, an incipient ectopia cordis: there is also a brownish discoloration here similar to that noted in the head region.

Histological examination reveals a beginning dissociation of the tissues, most noticeable in the nervous system, but the staining reactions are still fairly well preserved. The large defect is seen to be quite devoid of epithelial covering, but along its margins the body ectoderm stops very abruptly and is often heaped up into large prominent cell masses. The cells which make up these conspicuous masses are large and pale, irregularly polyhedral in shape, often several layers deep and seen to be derivatives of, or correspond with, the superficial periderm. There are indications of a similar, but less conspicuous, heaping up of cells along the border of the ventral tear, or the defect over the heart. The surface of the large defect on the head is smooth and even, and the limiting connective tissue cells often appear as a thin, well defined layer of squamous cells. Scattered among the superficial connective tissue cells there are considerable numbers of fairly large, roughly rounded, epithelioid looking cells, with small dark nuclei and of a peculiar brownish pigment, but the coloring material is very finely and evenly distributed throughout the whole cell and there are no indications of the usual pigment granules. These cells may account, in part at least, for the darker color of this part of the embryo.


Embryo No. 536

Only the embryo was obtained in this case, which represents the sixth pregnancy in a woman 30 years of age. The first pregnancy went to eight months, and this was followed by four miscarriages, from the fifth to the seventh months. The miscarriage in this last pregnancy occurred six or six and a half months after the last period. During the latter half of this pregnancy the patient was in poor condition, bad tonsils and infected teeth are noted in the history, also the possibility of lues. The placenta was said to be 50 mm. in diameter and to be markedly necrotic.

The greatest length of the embryo is 17.5 mm., its color is poor and there is some shrinkage, the superficial layers show numerous fine wrinkles and seem to be desquamating in many places. The head is rather small. In the sacral and lower lumbar region behind, there is a large, fairly regular area, somewhat more brownish in color, over which the superficial ectoderm seems to be missing. This area is very slightly depressed and its posterior margins are rather sharper and more symmetrical than the anterior. It measures about 4 mmm. in length by 3 mm. in width.

Sections through the embryo show the usual dissociation and lack of staining qualities. The brain is much more involved than the cord — even its major subdivision can hardly be recognized. The epidermis varies considerably in thickness and structure in different regions, but it is often made up of several much flattened stratified layers which show a marked tendency to separate from each other and also from the connective tissue below. There is widespread desquamation of the more superficial cells, while much of the epidermis gives the impression of being made up of stiff, hard cells, a condition in some ways not unlike those observed in Embryo No. 129, where there seemed to be a hyperkeratosis. In a few places, on the dorsum anterior to the defect, there are small “epithelial pearls” embedded in the epidermis. In addition, there are small scattered groups of cells which lie close to, or in contact with the deep surface of the epidermis, and in a few instances they seem to have been derived from the adjacent ectoderm. As noted in other cases, it is not always possible to identify the exact limits of the defect on microscopic examination, although in the gross specimen these were often quite definite and conspicuous. In some of these embryos the surface layers stain very intensely with hematoxylin, while the deeper structures may be quite unaffected. In this particular case the staining is especially intense in the general region of the defect and although structural details cannot be made out, there appears to be no very striking difference between the epidermis here and elsewhere on the body. That the surface epithelium of the back, particularly lower down, has been affected more, or in some other way, than the same layer of cells elsewhere, is indicated by the presence here of subepithelial groups of cells, of epithelial pearls and possibly also by the somewhat different staining reactions. In certain localities also there seem to be considerable amounts of pigment in the epithelium, but it is so masked by the stain that its presence is at least doubtful. Over most of the sacral defect the surface epithelium is quite intact, but near the end of the cord there are several places where it is lacking.


Embryo No. 161

Fig. 4. Embryo No. 161.

(Fig. 4). No history accompanied this specimen. The embryo is in very poor condition, the head being almost completely detached from the body, the greatest length not far from 12mm. The head appears small, particularly its anterior end, and in the face only the eyes can be distinguished. On the dorsum of the head, about in the region of the anterior part of the rhombencephalon, there is a transversely elongated, somewhat elevated, uneven mass which measures 3.5 mm. from side to side and 2.5 mm. from before backward. There is nothing to be made out on the surface and the color is substantially like that of the rest of the embryo. The outlines of this dorsal patch are quite definite and it is also fairly symmetrical. Sections through the head of the embryo show practically nothing that can be identified as the area seen in the gross in the back of the head. There is extensive dissociation everywhere although the nuclei still stain fairly well. The superficial ectoderm is very thin and for the most part quite inconspicuous.

The chorionic vesicle is of moderate dimensions, 33 by 26 mm., but it is thin and translucent and there are only a very few long, stringy villi. These villi lie close against the vesicle wall and are all directed the same way, as if smoothed out by some slipping or dislocation of the vesicle. The amnion is loosely fused with the chorion and its cavity contains a large amount of light flocculent precipitate.


The distal half of the cord is much smaller than the proximal part; no vessels can be seen anywhere.

Embryo No. 210

Fig. 5. Embryo No. 210.

(Fig. 5). In this case there had been eleven previous pregnancies, nine births at term and two miscarriages at the end of the first month. The mother was 40 years old and there was a menstrual history of fifty-one days. No cause was given for the abortion. The embryo, whose greatest length is 15 mm., is considerably deformed, the head is small and the face appears to be fused with the ventral surface of the trunk. The posterior end of the body is small and tapering, the extremities are somewhat retarded. The cord is short and straight, much distended and shows a small, pedunculated appendage near the embryo. In the dorsal midline, over the rhombencephalon there is a large thin-walled bleb, 3 mm. in diameter and elevated about 1 mm. above the surrounding surface of the body. The limiting walls of the bleb are rather steep and slightly undercut where they join the superficial ectoderm. No gross defects are to be seen around or beneath the superficial bleb and the surface layers of the body are elsewhere unaltered.

Although the embryo is in poor condition histologically, the dissociation of tissues is more marked in the region of the head and face than it is farther back, the brain having suffered most severely. Throughout the cord the dorsal half is beginning to break up, but the ventral portion is in much better condition. No definite changes of any kind can be seen in sections through the dorsal bleb. Both the superficial ectoderm and the underlying structures appear unchanged, except for their separation and the irregular foldings in the surface layer. The developmental damage in this instance is relatively slight, manifesting itself simply as an accumulation of fluid undermeath the ectoderm. There can be no doubt that even milder disturbances may occur here, as well as elsewhere, but they are latent, in a sense, and become conspicuous or recognizable only later in development.

The vesicle belonging to this embryo is substantially normal as regards its size, but its walls are thin, the villi very poorly developed and there is considerable hemorrhage under the decidual layer, by which it is completely surrounded. No vessels can be seen either in the sac or in the embryo.

Embryo No. 597 B

Fig. 6. Embryo No. 597 B.

(Fig. 6). This specimen, from a woman 37 years of age, is the smaller of two fraternal twins. There had been two previous pregnancies, the first going the term four years before, while the second terminated in abortion at about two months, possibly due to a fall. The present, or third, pregnancy also resulted in abortion, some eleven months after the preceding one. The last menstrual period began fourteen weeks before the abortion, but there is a history of menstrual irregularity for the two months preceding the last period, and of occasional morning sickness for two months before the abortion.

Judging from its condition the smaller fetus has been dead for some time, its larger companion is in very good condition but it is slightly distorted and has suffered a little from drying. The larger one is four times as long as the smaller, the sitting heights being 130 and 32.5 mm. respectively. The placenta and membranes of the larger one were not received. The smaller of the twins (No. 597 B), is light yellowish brown in color and the most superficial layers of cells are desquamating in shreds and sheets of considerable size. On both hands, the fingers, which are short and apparently fused together, are encased in what appears to be a much thickened epidermis. The feet seem to be normal, but the legs show a marked ventral convexity and the thighs appear rather short. In the midline over, or just behind, the vertex of the head there is a very conspicuous, symmetrical bleb which has an anteroposterior extent of 7mm. It is translucent and the regular outline of the head can be made out beneath it. The deeper structures are not involved. The cord is very much kinked and twisted, it varies considerably in size in different places, and obviously there has been no circulation through it for some time. Arising from the cord, close to its attachment to the fetus, are several large, thin-walled, almost pedunculated blebs or vesicles.

The placenta is quite out of proportion to the fetus, measuring 100 by 70 mm. Its fetal surface is irregular and nodular in appearance, due to the extensive subchorial hemorrhages. The amniotic fluid was turbid and discolored.

Embryo No. 407

Fig. 7. Embryo No. 407.

(Fig. 7). This is a rather typical stunted embryo in a large vesicle, with a menstrual age of nearly ten weeks. It was the first pregnancy and came from a woman 38 years old. For two days previous to the abortion there had been bleeding and abdominal pain. The embryo measures 7 mm. crown rump. It is very pale and of quite uniform color throughout. The head is very small, there are no indications of eyes, and only the first branchial arch can be made out. The limb-buds are small but fairly well developed, segmentation is only faintly indicated. Immediately above the anterior extremities there is a large bleb-like swelling on either side. In the dorsal midline, in the lower thoracic region, there is also a conspicuous elevation of the superficial layers over a small circumscribed area. Farther back, opposite the posterior extremities, there is a longer, but much less conspicuous swelling, not noticeable in the illustration.

The tissues of the embryo are in very poor condition, the nervous system, and more particularly its anterior part, being most severely affected. In the region of the superficial changes noted above, the constituent tissues are apparently unaltered, save for the separation of the epithelium from the underlying connective tissue, and the tearing and displacement of the former. All of the structures stain very poorly.

The sac is somewhat distorted and thin-walled. It measures 52 by 35 by 20 mm. It is very pale, practically free from blood and almost completely covered by thin, smooth decidua. Where exposed, the villi are rather slender and scattered but not especially abnormal. The amnion is large and somewhat thickened, and through a rent in it the embryo had escaped into the exocoelom. Blood vessels are not to be seen either in the embryo or in the membranes.

Embryo No. 442

Fig. 8. Embryo No. 442.

(Fig. 8). The specimen to be described here is a tubal pregnancy from a colored woman 26 years old. Four years ago there had been an abortion at three months, the cause being undetermined. For several years there had been a bilateral salPpingitis, also dysuria and frequency of urination for the past three months. The last menstrual period was ten weeks before operation, but throughout most of this time there had been spotting and pain in the left lower quadrant. At operation there was a chronic salpingitis on the right side, the uterus was small and forward and there were simple cysts in both ovaries. No mention is made of a corpus luteum.

Within the tube is a turbid amber fluid, apparently blood-stained. The embryo, which has a greatest length of 26 mm., appears fairly normal, although its color is not good. The eyes are large and conspicuous but the lids appear retarded in their development, due possibly to mechanical interference from the skin defect over the forehead. Below and internal to the right eye, there is a large pitlike defect.

In the midline behind, in the lower dorsal and lumbar regions, there is a slightly elongated area, about 7 mm. in length, over which the superficial layers seem to be wanting. This area is, in general, quite symmetrical, but a trifle more extensive on the right side. The right border is especially conspicuous, appearing as an irregular, ragged, elevated line of thickened or partially detached epithelium. In the anterior part of this area there is a smaller, darker patch, quite sharply marked off and situated almost exactly in the median line. On the anterior surface of the head, a short distance abcve the eyes, there is a large and very conspicuous, brownish discolored band, extending almost the entire width of the head. This frontal patch is much more striking in appearance than the one on the dorsum; it is also a little darker in color and more abruptly set off from its surroundings.

The cord is small, short and straight, its distal two-thirds is occupied by a large thin-walled, spindle-shaped enlargement, but at its attachment to both embryo and chorion it is very much constricted. No definite blood-containing vessels can be seen within it.

Sections through the posterior part of the embryo show that over most of the dorsal area noted above, the surface epithelium is intact. It stains very densely so that its structure cannot be determined, but it seems to be rather thicker than elsewhere. Along the margins of the area, however, there are numerous conspicuous thickenings in the ectoderm, as can be seen in Fig. 8. These thickenings are as a rule small and scattered, and they vary much in form and size from broad low mounds of cells, to slender, almost pedunculated outgrowths. The cells appear as if heaped up on the surface, without any involvement of the deeper layers. In general the subepithelial tissue seems rather denser and more fibrous on the back of the embryo, but it does not present the marked alterations to be seen in the frontal region. In the smaller central patch on the back the epithelium is definitely absent, and along its borders the limiting epithelium is thickened and ends abruptly, but the large, exuberant masses which are present farther back and more laterally are not seen here. Not only are the surface cells lacking here, but there is further evidence of disturbed development in the presence of numbers of large, rather wide clefts in the exposed connective tissue.


In addition to the spaces in the connective tissue of the dorsum there has been an extensive accumulation of fluid behind and on either side of the posterior end of the spinal cord, so that the latter appears to lie on the ventral wall of the large open cavity. At the very extremity of the cord there is a small irregular diverticulum which comes off from the ventral part of the central canal.

No essential difference can be seen in the epithelium over the frontal discoloration, as compared with that of the dorsal area, but in both cases the details are obscured by the intense staining. The former, however, shows only a very slight thickening of the ectoderm in a few places near the margins of the area. In the underlying tissues, on the contrary, there is a very striking difference. Running through the more superficial part of the sub-epithelial connective tissue there is what appears to be a rather denser stratum of the same tissue, but one which is stained almost as deeply as the ectoderm outside. This stratum is sharply delimited, near the center of the area it lies very close, if not in contact with the epithelium, but elsewhere there is interposed a thin layer of paler, normal connective tissue. Apparently this stratum was responsible for the very obvious and well circumscribed discoloration seen on the forehead in the gross specimen.

Embryo No. 652

Fig. 9. Embryo No. 652.

(Fig. 9). No menstrual history was obtained for this specimen, which came from a fibroid uterus. Even when fresh the condition of the embryo was not good, the color being a turbid brown, the greatest length a little over 15mm. There seems to be some desquamation of the surface epithelium, but this may be in part adherent precipitate. The head, especially its anterior part, is small, the mouth is widely open and its lateral angles may be torn somewhat. Trunk and extremities are fairly normal, although the latter appear slightly retarded.

On the dorsum of the head, over the anterior part of the rhombencephalon, there is a rather definite pale orange discoloration. It is symmetrically disposed as a transverse band which is best developed on the right side and somewhat indistinct in the midline. As far as can be seen the surface epithelium is intact and not materially altered.

The cord, which is small and straight, shows a small but prominent bleb close to the embryo. There is little evidence of vessels within the cord.


Although the tissues of the embryo are beginning to dissociate they still stain fairly well. The epithelium over the dorsum of the head is everywhere intact and shows no definite alterations in the arrangement or in the general morphology of its constituent elements. The discolored area seen in the gross specimen is, however, quite recognizable. It appears under low power, stained with eosin, as a fairly well circumscribed, pale yellowish pink region in the superficial ectoderm. There is not the even yellowish tinge seen in some of the connective tissue cells, in Embryo No. 665, or the very evident pigment granules which were present in Embryo No. 129. It looks more as if the region in question had been dusted over with a fine powdery substance, which, although it seems to have no definite relation to the epithelial cells, is confined to them and is not to be seen in the underlying tissues. This material is quite evenly distributed and its limits are rather definite. Scattered through these pinkish areas there are a few small, rather densely staining nuclei, much like those in the deeper tissues, but more numerous here than in the epithelium elsewhere. This peculiar material does not suggest pigment at all; it gives rather the impression of something which had been applied to the cells or even to the sections. The neighboring mesenchyme does not appear to be in any way involved.

The vesicle is essentially normal, the villi are numerous and well developed; the amnion may be slightly thickened and in the exocoelom there is abundant, coarse, stringy magma.

Embryo No. 167

Fig. 10. Embryo No. 167.

(Fig. 10). Except for a menstrual history of “about ten weeks,”’ and that the abortion was “‘not induced,” there were no data available on this specimen. The embryo is damaged somewhat, especially about the mouth and upper part of the trunk, and its color is decidedly poor. Its greatest length is 18.5 mm. The head, particularly its anterior end, is small, the mouth is wide open and there are deep tears on either side. Between the eyes are a number of small holes, or pit-like defects. The retinal pigment is paler than usual, and appears red rather than black. Both the anterior and posterior extremities, but particularly the former, are much retarded.

In the dorsal midline, about the region of the lower rhombencephalon, there is a small, transversely elongated, somewhat smoother, discolored area, slightly greenish in color. It is roughly reniform in outline, sharply marked off from the surrounding parts, slightly elevated and measures about 3 by 1mm. It does not appear to be a simple stain or discoloration and there is no evidence of any injury or defect. Farther forward, over the posterior part of the forebrain, not shown in the illustration, there is a smaller, more yellowish spot, irregular in outline and measuring about 2 mm. in diameter.

A little in advance of this second patch there are still two others of much the same character. These last mentioned, most anterior spots, lie close together, almost in the midline, high up on the forehead. They are rather darker in color, and even more conspicuous than the large area behind.

There is a most striking similarity to be found in the dorsal area of this embryo and the condition noted in Embryo No. 652. In both cases there is a very definite, transversely elongated, more or less discolored area, symmetrically disposed, exactly in the midline and lying over the rhombencephalon. In Embryo No. 167 the area is widest in the median line, while in No. 652 it is narrower there, and rather bilobed in appearance; in the former the area is a little farther back and it is also somewhat more conspicuous. Not only this, but the histological picture seems, with minor exceptions, to be essentially the same in both cases, the chief, and perhaps only, difference being that in No. 167 the histological changes are more marked and also more extensive. There is, in this embryo, the same powdery, or finely granular material which was found in No. 652. It is perhaps a little coarser, it stains more intensely and has more of a purple or violet color. This difference in appearance may be due in part to the larger quantities of the material present and to the fact that all of the tissues are stained more deeply with hematoxylin than in the other embryo. Not only is this material much more abundant and more closely packed, but most of it is found in the connective tissue immediately below the epithelium, whereas in the earlier case it was confined to the epithelium. In the present embryo it is likewise present in the epithelial cells, but it is much more marked in the underlying tissue. In its distribution in this case it seems much more sharply circumscribed, due apparently to the larger and denser masses involved. The three areas over the forebrain show the same features — if anything the involvement of the mesenchyme is even more marked. Here, as in the previous case, the epithelium is intact, but there are a few small thickenings around the margins of the area, especially the dorsal area. Over the frontal areas the epithelium appears quite unchanged, but at one or two points there are slight defects, apparently postmortem tears.


The vesicle of No. 167 is of normal size, but it is very thin and villi are practically absent, except for one large clump where they are numerous and thickly set. The villi present are long and somewhat swollen, but there are no globular forms. No vessels can be seen anywhere.

Embryo No. 404

Although this is a tubal pregnancy, the embryo is in much better condition than most of the specimens in this series. Its greatest length is 21.5 mm. and, except as noted below, it appears perfectly normal. This was the third pregnancy in a woman of 27 years. There was nothing out of the ordinary in the first two. The last period was sixty-two days before operation and there had been acute pains in the right lower quadrant for a month. The embryo and amnion were all that were obtained.

The only point to be noted concerns the very posterior end of the body. Here, in the midline of the back, over the lower lumbar and sacral regions, there is an area about 6 mm. long and 2 mm. wide reaching almost to the end of the tail, over which the surface epithelium is apparently missing. The margins of this defect are quite smooth and regular, both its anterior and posterior limits are symmetrically rounded, and there still seems to be some tissue covering the cord. It does not seem possible that this loss of tissue could be due to simple mechanical violence. In the sections there is little to be seen except the absence of the surface cells in the region of the defect. There is some suggestion of a thickening in the epithelium along the margins, but nothing very definite. The exposed connective tissue is unaltered.


Embryo No. 671

Fig. 11. Embryo No. 671.

(Fig. 11). There are no data on this specimen, except that the abortion was probably self-induced. The embryo, which has a greatest length of 25 mm., is well developed and in fair condition, but there are accumulations of fluid under the epidermis and a number of superficial hemorrhages. Over the posterior aspect of the neck and lower part of the head there is a very extensive area in which the superficial layers are raised up in an enormous bleb. This region is fairly well circumscribed and quite symmetrical. The outlines of the underlying structures, which appear normal, can be made out quite readily through the thin walls of the bleb. On the left side there is a sharply circumscribed mass of blood covering most of the lateral wall of the bleb on the inside. It appears to have simply settled down into this position, due to the embryo lying on the left side. There is widespread hemorrhage in the superficial tissues on the right side of the face and lower part of the head and a few smaller hemorrhages on the left side. Two or three small, deepseated hemorrhagic spots can be seen within the bleb, which may be the source of the blood clot on the left side. In the lower thoracic and upper lumbar regions there is a separation of the superficial layers over a considerable extent in the midline, but this is much less conspicuous than the conditions just noted and there is no extravasation of blood. Both upper extremities show considerable vascular engorgement and some actual hemorrhage, especially on the right side.

The chorionic vesicle is rather large for the embryo, and is covered practically everywhere with long, thick-set villi. It is not entirely normal, however, since many of the villi are swollen and irregular, and smaller cystic forms are quite plentiful; the vessels within are quite conspicuous.

Embryo No. 513

Like Embryo No. 404 this is also a tubal pregnancy, but it was the first pregnancy in a woman of 32 who had been married for ten years.

Although this embryo is essentially normal it is not in quite so good condition as No. 404. Its greatest length is 18.5; mm. In the midline behind, just below the fourth ventricle, there is a small oval patch about 4 mm. from side to side and 3 mm. in its anteroposterior dimension. It is not exactly in the midline, but slightly to the right, and obviously the surface layers have been torn away.

From the sections one might conclude that the defect on the back of the head is simply a local accident in a process which is much more widespread. This more extensive condition appears as a marked edema in the subepithelial connective tissue. It is peculiar, in that it is quite symmetrical on the two sides of the body and over the dorsum, and also because the great enlargement of the connective tissue spaces is confined to the more central layers of the mesenchyme, the more superficial as well as the deeper layers being unaffected. The later or final stages of the process are represented by the tearing apart of the much attenuated mesenchyme and the confluence of the spaces thus formed. This is what has evidently happened on the dorsum where there is a very extensive undermining of the surface layers. At the site of the defect, the outer wall of this fluid-filled cavity has given way, or been torn, and in addition some of it is actually missing. This anasarcous condition extends from the posterior part of the head downward along the sides of the neck and behind the shoulders into the lateral body walls. It encroaches only slightly upon the face in front of the ear. The dorsal midline is not involved, except in the region of the head. The connective tissue and covering epithelium show no changes except the stretching and distortion in the former. It should be noted that the condition is most marked over the dorsum, that it is here only that tearing or loss of tissue has occurred, and also that in the other embryos which are affected in this way it is only the back that is involved.

The vesicle measures 30 by 28 mm., not including the villi. It is somewhat shrunken and pale brownish yellow in color. About half of its surface is covered by long, close-set villi, while the remainder is almost bare. The villi are not normal. Many of them are enlarged and swollen, while many show fine threads like branchings. Bulbous and globular enlargements are common, as well as great numbers of fine, short, side branches. The vessels in the larger villi are more conspicuous than usual. The interior of the sac appears normal.

Embryo No. 611

Fig. 12. Embryo No. 611.

(Fig. 12). This specimen came from a hysterotomy ten weeks after the last period in a woman 31 years old. It was the second pregnancy and was indicated on account of pelvic deformity which had caused considerable difficulty at the time of the first labor. There had been slight nausea for three weeks preceding the operation. The left tube was found markedly adherent to the lateral pelvic walls and there were three cysts attached to its fimbriated end.

The embryo, which measures 23 mm. greatest length, is apparently normal, although its condition is not quite what it might be. There are only a few points which need to be noted. In the midline, over the cerebellum, there is a minute, thin-walled bleb, except for which the entire dorsum is intact and normal. There are some small scattered ecchymoses behind the left ear, on the left shoulder and on the lateral thoracic wall behind. As seen in ventral view there is a fullness about the head, behind and below the ears, suggestive of edema.

From the sections it can be seen that the embryo is not as normal as it appeared to be. In the region of the bleb shown in the illustration, the epithelium is separated from the underlying tissue. Farther forward, however, there is another, even more extensive area in the midline where there is an accumulation of fluid, but in this case it is located deeper, within the connective tissue. In addition to these median spaces there are two wide clefts on either side of the midline over the forebrain. Along the lateral aspects of the brain, farther back, the connective tissue spaces are very much dilated and in many places there are wide-open spaces, the condition being much like that seen in Embryo No. 513, but not as severe. Except for these spaces the tissues appear normal, but most of the blood vessels are very much engorged with blood, even the smallest ones.

The vesicle is rather small and is thickly covered with long, richly branched villi which are often matted together. Most of the villi are swollen and irregularly dilated, but the changes are not as marked as in No. 513.

Embryo No. 682

The present series of cases may be appropriately brought to a close with this specimen. The history is somewhat uncertain, but this appears to have been the first pregnancy. The menstrual age is given as two and a half months and the abortion might have been induced. The color and condition of the embryo are not especially good. The greatest length of the embryo is somewhat uncertain but may be taken as not far from 15 mm. The anterior end of the head seems rather small, the mouth is more widely open than usual. Although blood vessels can be seen in the cord, they are hardly distinguishable at its attachment to the membranes. The cord itself is smaller than normal, and most of it is occupied by a large, irregular bleb. On the dorsal surface of the left foot-plate there is an extensive, diffuse, but rather mild hemorrhage.

Exactly in the midline of the back, in the slight concavity behind the midbrain, just in front of the cerebellum, there is a faint brownish, linear discoloration, at right angles to the median plane and not over 1.5 mm. in length. It appears as a narrow, slightly irregular, pigmented line, but its exact nature cannot be made out. Attempts to photograph this dorsal patch were unsuccessful; not only this, but later examination of the specimen, in the gross, showed little or nothing which could be positively identified as the fine line seen at an earlier date. This is the smallest and least noticeable alteration in the midline that we have encountered in any of our cases.

The chorionic vesicle is of fair size, 45 by 26 by 20 mm. Its walls are thin and the villi, which are few in number, are scattered along one side and at one end. Many of the villi are slender and stringy, while others are definitely dilated and bulbous. The amnion is already fused with the chorion.


Discussion

From the foregoing descriptions of seventeen specimens, it is evident that peculiar conditions obtain in the dorsal midline. Early development may be compromised or deranged in a variety of ways, but the effects are most often in evidence in that part of the body from which is formed the central nervous system. Milder derangements may show themselves only at a later date, or only in those structures which cover in the neural tube behind. The extreme susceptibility of the early nervous system to unfavorable influences, whether occurring in nature or under experimental conditions, has long been recognized, while its significance in human development has been abundantly illustrated by Mall,?)* Mall and Meyer,‘ as well as by many other writers. Much less attention, however, has been given to the comparatively slight defects which abound in this region. From our own experience these milder cases may be more common than the more severe ones, particularly during the first two months of development. The possible significance at the end of development of some of these less conspicuous deviations from the normal will be considered on another occasion, likewise the finer histological details exhibited by the tissues affected.

The extensive works of Mall and Meyer, referred to above, contain numerous examples of defective midline development. They also bring out very clearly the great vulnerability of this region, as shown by the high percentage of cases in which it is mainly or alone involved. While our own series has been selected on the basis of minor defects, and for these only, if they occur in the midline, all sorts and degrees of maldevelopment, regardless of their character or location, are included in Mall’s and Meyer’s material. For this reason many, perhaps the majority, of their cases of midline defects represent severer degrees of damage than are encountered in our present series. There are, however, in this Carnegie material, a considerable number of cases in which the tissue alterations seem to correspond more or less closely with conditions as we have found them. There is frequent reference to blebs and blisters, loss of superficial epithelium, thickening of the connective tissues, abnormal pigmentation, or the presence of papillomatous outgrowths. Mall speaks repeatedly of ulcerations, particularly on some part of the head, but just how these “ulcers” differ from other defects, which may have a similar location, is not always clear. But neither Mall nor Meyer was especially concerned with any particular type of malformation; the primary object of their investigations was of a more general nature, while the amount and variety of the material to be considered made all but impracticable any detailed account of the findings in each individual case. We cannot be sure, therefore, to what extent the anomalous histological conditions which we have encountered in our material might be duplicated in their specimens. Neither is it always apparent that the defects which they describe are as conspicuous in the gross specimen, as sharply delimited and symmetrical, or as exactly located in the midline as many of those which we have found. Certainly a number of our cases are very similar, even in the gross. Mall? (Fig. 6b) shows an unusually large and sharply defined bleb on the back of the neck of Embryo No. 1523, while Embryo No. 2261 (Fig. 72) in Plate 5, Mall and Meyer, is almost a replica of our Embryo No. 671.


Although it is possible to say why the dorsal midline should show a special predisposition to defective development, it is not so easy to say why some of the minor defects should show a predilection for a particular part of the dorsum. It would appear, however, from our own cases as well as from the Carnegie material, that the back of the head, perhaps more exactly the region over the anterior rhombencephalon and midbrain, is more often the seat of defects, usually slight, than any other part of the back of the head. It can hardly be argued that this part is more exposed to external influences than any other. It is more likely that the real explanation is to be found in the inherent factors which govern the growth and differentiation of the human brain and of the tissues which surround it.

We have been interested in these minor defects, partly on account of their relative frequency, but mainly because of the role they might play in those cases where development is not interrupted. It is, of course, not possible to say just what might have been the final result in any particular case. In a few instances one can recognize what may be earlier and later stages of the same condition, but in the individual case there is nothing to indicate whether the process is progressive or regressive or at a standstill. Where the whole embryo is markedly pathological, moribund or even dead, one might suppose that the process would be progressive and terminate only with the death of the cells or tissues involved. In the more normal embryos, however, it would not seem possible to make any prediction, since the greater vitality and growth capacity of the cells might bring about more or less perfect healing on the one hand, or a more pronounced reaction to the causative agent on the other. In some cases the damage seems to be very slight and complete restitution might have been possible, while in others the later stages might have shown local cutaneous defects, or even more deep seated disturbances. Certain aspects of this question will be taken up in a subsequent paper.

In the often sharply located disturbances seen in our specimens there is something akin to the “focal deficiencies” which Streeter * has shown to be of such importance in the development of the extremities. Although the predisposing factors may be different in the two sets of cases, it is quite possible that the more immediate, inciting causes may be more closely related. Certainly the limbs, and more especially their distal segments, show a marked susceptibility to unfavorable influences, and in this respect they are in a class with the midline of the back. The reasons for their exceptional vulnerability, however, are not as apparent.

The recognition of predisposing and exciting factors in maldevelopment is tantamount to saying that normal fertilized ova or normal embryos may give rise to malformations. This is undoubtedly true, and Mall was particularly insistent upon it, but in his writings the emphasis is on the exciting or contributing causes rather than upon the deeper predisposing influences. Streeter is much more specific in his reference to eggs of different quality, of varying capacity or potentiality for development, not only as a whole, but in their various derivatives and at different stages of development. Eggs are no more alike or equal than are the individuals from which they were obtained, or the future forms into which they might have grown. This perfectly natural and normal variability in eggs or embryos expresses itself, in one form, as a varying susceptibility, or resistance to unfavorable influences, and also in the specific type of reaction which such influences may bring out. In the present series of cases we have been dealing with a natural vulnerability of a certain part of the body. It is altogether probable, however, that this vulnerability is not the same in all cases — it may vary in degree or in location, as well as in the disposition of the tissues to react in one way or another. This variability and vulnerability is essentially germinal in character, and for that reason the hereditary possibilities cannot be overlooked.

As pointed out by Streeter, the quality of the egg, and its inherent germinal integrity, determine very largely whether it will succumb early in life, eke out a more or less precarious and misshapen existence, or continue in health and vigor to old age. Even under the most favorable conditions maldevelopment may occur. The more environmental conditions deviate from the normal, the more severe will be the tax upon those factors which should ensure proper development, and the easier it will be for normally latent influences to make themselves felt.

Although the exact role of environmental disturbances in the etiology of maldevelopment is not always clear, such disturbances are especially frequent and conspicuous in young monsters and pathological embryos. Among others, Mall and Meyer have written extensively on the alterations in the embryonic membranes which are so frequent and characteristic, and which undoubtedly play an important part in disrupting or even terminating normal development. As we have nothing out of the ordinary to contribute here, we shall confine ourselves to a brief survey of some of the more general features presented by our material.

There are many ways in which this material is typical of maldevelopment in the human being. Most of the specimens are from the second month. In the cases where the menstrual age is known, it varies enormously, from five and a half weeks to six months, the average being eleven weeks. As a rule the membranes are not normal; the vesicles are often too large, the villi very frequently show hydatid changes in varying degree, or they may be few and small and fibrous. In many cases there is no evidence of any real vascular connection between the embryo and chorion, while extensive subchorionic hemorrhages are very common. The obvious circulatory disturbances may be responsible for the presence of hydramnios, early fusion of amion and chorion, changes in the character of the magma and in the composition of the fluid within the vesicle. In addition to the typical midline defects, many of the embryos show other localized anomalies, while in the majority of them the general condition of the embryo has been considerably altered. The internal disorganization and general disruption, which is so often encountered, is in no sense a teratological condition, but rather a pathological one, although the underlying factors may be much the same. Many of the peculiar skin conditions described above are pathological rather than teratological, if one chooses to draw a line between them, for the inherent vulnerability of certain tissues is quite as much a problem for the pathologist as it is for the teratologist. The various anomalous conditions which are exhibited by the superficial tissues are of very great interest. Two points only need be mentioned here. In the first place, the relatively great expanse of surface exposed to the amniotic fluid would seem to provide some measure of sustenance even after the embryonic blood circulation had ceased entirely. This would apply only to the outermost cells of the body, which might, on this account, be able to prolong their life after the death of all of the deeper structures. In other words, the skin or covering cells of the embryo might, under some circumstances, be the last to die off. The other point is that the amniotic fluid might conceivably act as an irritant to the superficial cells. There seems to be evidence that its character and composition may be altered and in some of our cases one gets the impression that the epithelium has not been living and differentiating under normal external conditions. This hypothetical irritation may, of course, be very mild, behaving more like a stimulant than anything else.

Doubtless the fact that the circulation is so often impaired explains why hemorrhages are relatively infrequent. They occur only in the better preserved, more normal specimens, and here mainly in the region of the head. We have found no indications of hemorrhage or bleb formation in the extremities at all comparable with those described by Bagg * in mice. It may very well be that hemorrhage is less frequent on the back than in the hands or feet, on account of the earlier and greater vascularity of the latter. It is also possible that the relatively poor blood supply of the structures dorsal to the nervous system, especially early, may stand in some relation, or contribute something to the frequency of defects in this region.

It may be objected that some of the conditions described in our embryos are essentially postmortem changes and that it is not possible to attach any particular significance to them. There may be some small justification for this criticism, since, in the very nature of the case, we are dealing, for the most part, with material which is neither wholly normal nor perfectly healthy. In many of our cases, indeed in the most interesting and suggestive ones, there can hardly be any question of postmortem alterations and the picture is anything but that of cell death and a cessation of activity. In some instances there is evidence of hyperactivity, rather than anything else, and indeed some dorsal patches described seem to have retained their vitality longer than any other parts of the embryo. Although we have excluded, as far as possible, all cases which seemed to show only maceration or other moribund changes, it is quite possible that these influences may have contributed something to the general character of the picture in some instances. The variety of conditions observed, and the fact that they occur typically and almost exclusively in the dorsal midline, would indicate the importance of internal rather than external factors in their production, and least of all of postmortem influences.

In the first number of this series on the pathology of development (Ingalls,1) we have considered in some detail the general underlying biological and genetic principles out of which flow, naturally and inevitably, certain developmental risks. These risks, or the opportunities for various developmental derangements, are especially in evidence in the structures dorsal to, and including, the central nervous system. It would appear also that these parts of the body are especially sensitive and susceptible in man, and this instability, in a sense this relative vulnerability, may express itself in an almost endless variety of ways. The factors at work here are internal, inherent in the nature of the organism, essentially hereditary in character, although altered or disturbed external, environmental conditions may be necessary for, or at least conducive to, abnormal results.

In the present communication we have been concerned especially with some of the milder types of maldevelopment of the back and head, as exhibited in human embryos of the first two months. They are of interest particularly because these cases may very well represent the earliest stages of some of the anomalous conditions which are encountered in this region at term or even at any time of life. In many of our cases the dorsal defects are very slight and could have contributed little or nothing toward the interruption of the pregnancy, which, but for other reasons, might have continued to term. What would have been the final outcome in these cases is, of course, very problematical. Apparently there is, in most instances, either early death of the embryo or fetus from other causes, or a complete healing and restitution of the parts affected. It is quite possible, however, that the damage may be so slight that it is entirely overlooked or its real significance may not be recognized. As noted previously, anomalous or defective conditions of the dorsal midline, varying greatly in degree and character, but not sufficiently severe to compromise further growth and development, are by no means uncommon during the early weeks of intra-uterine life. While many, perhaps most of these cases, fail to go to term, and among those which do reach maturity there may be, in some instances, a more or less complete or adequate resisiutio ad integram, there remain a certain number in which the initial damage has been sufficiently severe, or of such a character as to render repair or suitable compensation difficult if not impossible. These are the cases which assume a definite clinical, often surgical importance. They are characterized not by any uniformity in the pathology, or in the structural features exhibited by the conditions in question, but rather by their predilection for the dorsal midline, perhaps more particularly the region of the head and neck.

References

Ingalls NW. Studies in the pathology of development. I. Some developmental risks, the dorsal mid-line. (1932) Quart. Rev. Biol. 7: 48.

Mall FP. Normal plates of the development of vertebrates. Anat. Rec, (1908).

Mall FP. On the frequency of localized anomalies in human embryos and infants at birth. (1917) Amer. J Anat. 22:49-72.

Mall FP. and Meyer AW. Studies on abortuses: a survey of pathologic ova in the Carnegie Embryological Collection. (1921) Contrib. Embryol., Carnegie Inst. Wash. Publ. 275, 12: 1-364.

Streeter GL. Focal deficiencies in foetal tissues and their relation to intrauterine amputation. (1930) Contrib. Embryol., Carnegie Inst. Wash. 22: 4.

Bagg HJ. Hereditary abnormalities of the limbs, their origin and transmission. II. A morphological study with special reference to the etiology of club-foot, syndactylism, hypodactylism, and congenital amputation in the descendants of X-rayed mice. (1929) Amer. J Anat. 43(2): 167-219.

Plates

Plate 99

Ingalls1932b plate99.jpg

Fig. 1. Embryo No. 83. Greatest length about 7mm. Open neural tube in sacral region. Facial features distorted, heart exposed.

Fig. 2. Embryo No. 46. Greatest length 14.5mm. The entire body is very much malformed. Almost the whole of the dorsum is markedly altered or defective. The deep triangular cavity is due to the postmortem loss of tissue.

Fig. 3. Embryo No. 129. Greatest length 12mm., dorsal view. Irregular, roughly circular discolored area in the anterior part of the back. Entire body badly stunted and deformed.

Fig. 4. Embryo No. 161. Greatest length about 12mm. Symmetrically located, transversely elongated area over the anterior part of the rhombencephalon. Embryo in very poor condition.

Plate 100

Ingalls1932b plate100.jpg

Fig. 5. Embryo No. 210. Greatest length 15mm. Large thin-walled bleb in the midline over the rhombencephalon. Much deformity in the body generally.

Fig. 6. Embryo No. 597 B. The smaller of a pair of binoval twins, greatest length 32.5mm. Very large, rather thick-walled bleb in the midline of head, just behind vertex. Extensive desquamation, malformed hands and cord.

Fig. 7. Embryo No. 407. Greatest length 7 mm. Small bleb-like elevation of epithelium in the midline of the back. Head small and malformed.

Fig. 8. Embryo No. 442. Greatest length 26 mm. Dark patch in lower dorsal region; on the right and below can be seen the borders of the larger area. Laterally the epidermal thickenings are very conspicuous. There is also a very definite transverse band across the forehead.

Plate 101

Ingalls1932b plate101.jpg

Fig. 9. Embryo No. 652. Greatest length 15 mm. Dorsal view of anterior end of embryo to show the transverse discolored band just behind the midbrain.

Fig. 10. Embryo No. 167. Greatest length 18.5mm. Very conspicuous, sharply defined, discolored area over the rhombencephalon. There is a similar smaller patch over the vertex and two paired spots on the upper part of the forehead.

Fig. 11. Embryo No. 671. Greatest length 25 mm. Enormous blood-stained bleb on back of head and neck. Jn the lower thoracic region there is a much smaller one. Small ecchymoses on face and arm.

Fig. 12. Embryo No. 611. Greatest length 23 mm. Minute, translucent bleb over the cerebellum. Ecchymoses on head, shoulder and trunk.


Cite this page: Hill, M.A. (2021, September 24) Embryology Paper - Studies in the pathology of development 2 (1932). Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Paper_-_Studies_in_the_pathology_of_development_2_(1932)

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