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According to one investigator the defective fusion of the margins of the neural groove is due to deficient growth of the blastoderm (von Recklinghausen). Another view is that the separation between the neural tube and the adjacent ectoderm is incomplete (Torneux). Still another investigator considers the defective development due to some primary defect in the germ (Ziegler). Experimental studies on the frog's egg suggest to another observer that spina bifida is caused by defective closure of the blastopore (Hertwig). Recently it has become possible to produce spina bifida at will in some of the lower Vertebrates (frog, Axolotl) by treating the developing eggs with a solution of sodium chlorid (Hertwig). At the same time other defects in the nervous system (anencephaly) are produced. In these experiments the malformations follow retarded closure or lack of closure of the neural tube.  
According to one investigator the defective fusion of the margins of the neural groove is due to deficient growth of the blastoderm (von Recklinghausen). Another view is that the separation between the neural tube and the adjacent ectoderm is incomplete (Torneux). Still another investigator considers the defective development due to some primary defect in the germ (Ziegler). Experimental studies on the frog's egg suggest to another observer that spina bifida is caused by defective closure of the blastopore (Hertwig). Recently it has become possible to produce spina bifida at will in some of the lower Vertebrates (frog, Axolotl) by treating the developing eggs with a solution of sodium chlorid (Hertwig). At the same time other defects in the nervous system (anencephaly) are produced. In these experiments the malformations follow retarded closure or lack of closure of the neural tube.  


==DEFECTS IN THE REGION OF THE FACE AND NECK, AND THEIR ORIGIN==
==Defects in the Region of the Face and Neck, and their Origin==


Associated with malformations of the brain there is a group of defects which involye the eyes and nose, and to which the term cyclocephaly has been applied. The cerebral hemispheres are derivatives of the fore-brain. Sometimes they fail to develop properly and are represented by a single mass occupying a considerable portion of the cranial cavity. The eyes primarily represent lateral, symmetrical outgrowths from the fore-brain vesicle. If the cerebral hemispheres fail to develop, the development of the eyes is profoundly influenced. Instead of being widely separated there may be any degree of malformation from a mere narrowing of the distance between them to a complete fusion into a single organ within a single medial orbit synophthalmia or cyclopia. Within this orbit the eye may possess double or partially blended corneae, pupils, lenses, and optic nerves, or it may have single structures.  
Associated with malformations of the brain there is a group of defects which involye the eyes and nose, and to which the term cyclocephaly has been applied. The cerebral hemispheres are derivatives of the fore-brain. Sometimes they fail to develop properly and are represented by a single mass occupying a considerable portion of the cranial cavity. The eyes primarily represent lateral, symmetrical outgrowths from the fore-brain vesicle. If the cerebral hemispheres fail to develop, the development of the eyes is profoundly influenced. Instead of being widely separated there may be any degree of malformation from a mere narrowing of the distance between them to a complete fusion into a single organ within a single medial orbit synophthalmia or cyclopia. Within this orbit the eye may possess double or partially blended corneae, pupils, lenses, and optic nerves, or it may have single structures.  
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The branchial arches (apart from the first which has already been considered) and the branchial grooves are also subject to defective developmental processes. Malformations of the ear, with closure of the external auditory meatus, due to abnormal development of the first groove and surrounding parts, are sometimes met with either alone or in connection with other facial defects. Cervical fistula are the results of imperfect closure of some of the grooves along with rupture of the membranes that separate the bottoms of the external grooves from the bottoms of the internal grooves or pharyngeal pouches. The fistula may be complete, that is, there may be a communication between the pharyngeal cavity and the exterior; or it may be incomplete, opening either into the pharynx, or on the surface of the body. The internal opening of a cervical -fistula is usually in the lower part of the pharynx or in the posterior palatine arch near the tonsil. The external opening varies in position. It is usually situated near the sterno-clavicular articulation, or at the inner or outer edge of the sterno-mastoid muscle. The majority of cervical fistulae are probably derived from the second branchial groove. They all have the form of narrow canals lined with mucous membrane. Medial cervical fistulae, the external openings of which are situated in the medial line, are rare.  
The branchial arches (apart from the first which has already been considered) and the branchial grooves are also subject to defective developmental processes. Malformations of the ear, with closure of the external auditory meatus, due to abnormal development of the first groove and surrounding parts, are sometimes met with either alone or in connection with other facial defects. Cervical fistula are the results of imperfect closure of some of the grooves along with rupture of the membranes that separate the bottoms of the external grooves from the bottoms of the internal grooves or pharyngeal pouches. The fistula may be complete, that is, there may be a communication between the pharyngeal cavity and the exterior; or it may be incomplete, opening either into the pharynx, or on the surface of the body. The internal opening of a cervical -fistula is usually in the lower part of the pharynx or in the posterior palatine arch near the tonsil. The external opening varies in position. It is usually situated near the sterno-clavicular articulation, or at the inner or outer edge of the sterno-mastoid muscle. The majority of cervical fistulae are probably derived from the second branchial groove. They all have the form of narrow canals lined with mucous membrane. Medial cervical fistulae, the external openings of which are situated in the medial line, are rare.  


It sometimes happens that during the closure of the branchial grooves portions of the walls of the grooves becomes enclosed within the walls of the pharynx, that is, within the sides of the neck. This abnormal process results in various forms of cysts and tumors. The most common are simple retention cysts, known as branchial or branchio genetic cysts, which vary from small insignificant structures to large tumors. If derived from the external branchial furrows, they are dermoid in character, lined with ectodermal derivatives, and contain sebaceous material. If derived from the internal furrows, they contain mucous fluid, the lining epithelium is likely to be columnar and is claimed by some to be ciliated.  
It sometimes happens that during the closure of the branchial grooves portions of the walls of the grooves becomes enclosed within the walls of the pharynx, that is, within the sides of the neck. This abnormal process results in various forms of cysts and tumors. The most common are simple retention cysts, known as branchial or branchio genetic cysts, which vary from small insignificant structures to large tumors. If derived from the external branchial furrows, they are dermoid in character, lined with ectodermal derivatives, and contain sebaceous material. If derived from the internal furrows, they contain mucous fluid, the lining epithelium is likely to be columnar and is claimed by some to be ciliated.


==DEFECTS IN THE THORACIC AND ABDOMINAL REGIONS, AND THEIR ORIGIN==
==DEFECTS IN THE THORACIC AND ABDOMINAL REGIONS, AND THEIR ORIGIN==

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Bailey FR. and Miller AM. Text-Book of Embryology (1921) New York: William Wood and Co.

Contents: Germ cells | Maturation | Fertilization | Amphioxus | Frog | Chick | Mammalian | External body form | Connective tissues and skeletal | Vascular | Muscular | Alimentary tube and organs | Respiratory | Coelom, Diaphragm and Mesenteries | Urogenital | Integumentary | Nervous System | Special Sense | Foetal Membranes | Teratogenesis | Figures
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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)



Teratogenesis

--Mark Hill 13:39, 17 January 2011 (EST) Please note once again the historic and dated nature of this textbook both in terminology and in understanding of teratogenic mechanisms.


Malformations Involving More than One Individual

Classification, Description, Origin.

To give a complete list of the numerous malformations in man, even of those which affect the external form of the body, is obviously beyond the scope of this book. In this chapter it is the purpose of the writers merely to describe in a general way the most striking malformations and discuss briefly the causes underlying the origin of malformations. For further details concerning the subject the student's attention is directed to " References for Further Study " (p. 624).

The classification of malformations is attended by great difficulties. This is due mainly to the fact that their complexities are not wholly understood. It is due also in a measure to the fact that, apart from certain malformations which always occur in like manner in different individuals, there are so many irregularities and deviations from any type that might arbitrarily be chosen. The classification made by St. Hilaire three-quarters of a century ago, although apparently complete, showed many incongruities as teratology became more firmly established upon an embryological basis. Later Bischoff formulated a division based upon the embryological significance of malformations. This in turn was elaborated by Forster, and Forster's scheme has been adopted by Marchand and others. As knowledge concerning teratogenesis is added to, it may be that further changes in classification will be necessary, especially in view of the fact that much light is being thrown by experimental methods upon the origin of malformations.

Marchand's scheme of duplicate monsters is given here as a convenient one for a comprehensive view of anomalous conditions affecting two individuals. I. Both bodies derived from anlagen which developed from one ovum and which were originally similar and symmetrical: Symmetrical duplicity. A. Both bodies originally complete : Complete duplicity.

1. The two bodies remain separate; union confined to chorion* Twins; free duplicities.

a. Both bodies formed alike, each capable of living: Equal monochorionic twins.

b. One body normal, the other abnormal or much malformed: Unequal monochorionic twins.

2. The two bodies united; formed alike (equal), or one remains more or less rudimentary (unequal) : Twins joined together; duplicate monsters.

a. Union confined to lower end of body : Double monsters with posterior union; anterior duplicity.

b. Union confined to middle of body, or extending from middle forward: Double monsters with middle union.

c. Union limited to upper end of body, or extending from upper end downward: Double monsters with anterior union; posterior duplicity.

B. Duplicity does not affect entire anlage, but only a part : Incomplete duplicity.

1. Two incomplete anlagen (or primitive streaks) pass over into a single anlage: Posterior incomplete duplicity.

2. An originally single anlage forms by dichotomous growth two separate upper (anterior) ends: Anterior incomplete duplicity.

In addition: Triplicity, quadruplicity, etc., (multiplicity). II. Both bodies derived from two originally dissimilar, asymmetrical anlagen, of which one, always rudimentary, becomes more or less enclosed and nourished by the other: True parasitic duplicity; asymmetrical duplicity.

In addition: Teratoid tumors.

Symmetrical Duplicity

As seen from the foregoing scheme, there are included under this head double forms in which both embryos develop within a single chorion (monochorionic twins), and in which the bodies may be distinct and separate (complete duplicity) or may be united (incomplete duplicity). In complete duplicity each embryo usually possesses its own amnion and umbilical cord, but both are attached to the same placenta. In such cases the two individuals probably developed from one fertilized ovum and thus received equivalent chromatin which, with similar nutritional conditions, guided the formation of equal monochorionic twins. They may grow to maturity, and they always bear a remarkable resemblance to each other in physical features and in mental characteristics and are always of the same sex. More commonly, however, the development of separate monochorionic twins is unequal, caused probably by dissimilar chromatin and nutrition. In some instances the less favored individual is but slightly affected, so that it may be born and be able to maintain an independent existence. On the other hand, the nutrition of one embryo may be so seriously impaired that it dies. When death occurs during the earlier months of pregnancy the dead embryo is subjected to pressure by the living one and is sometimes distorted and flattened into a thin mass known as a fcetus papyraceus.

Equal growth of monochorionic twins implies an almost perfect nutritive balance, since both embryos derive their nourishment from the same placenta. Any condition that disturbs the nutritive balance tends to affect adversely the less favored embryo, so that development does not proceed equally (unequal monochorionic twins). One of the first consequences of such a disturbance may be an impaired or arrested development of the heart, in which case the weaker embryo may become an acardiac monster.

This condition does not necessarily imply the absence of the heart in the affected twin; for it may possess a functionating heart, or it may become an amorphous mass of tissue which derives its total blood supply through the action of the heart of the stronger twin, or there may be any form between the two extremes. In any case the acardiac monster acardiacus receives its blood wholly or in part through the agency of the stronger heart.

Acardia is always accompanied by a so-called "reversal of the circulation;" and there are three periods at which it may originate, (i) It may originate before the heart develops. As is well known, the heart appears independently of the area vasculosa and joins the vessels secondarily (p. 191). If, for any reason, the heart of one of the embryos fails to develop, anastomoses may occur between the vascular anlagen of the two vascular areas and consequently the normal embryo assumes the duty of nourishing the other. The latter becomes an acardiac monster. (2) It may originate after the heart has begun to develop, but before the placental circulation is established. If, for any reason, the heart of one embryo should cease to develop further, there would probably be sufficient anastomoses between the vitelline vessels of the two embryos to enable the affected embryo to live and become an acardiac parasite. In this case no placental circulation would develop in the parasite. (3) Acardia may originate after the establishment of the placental circulation. Since there is but one chorion or placenta for both embryos there is naturally a communication between the two circulations in the chorionic villi. There are also likely to be anastomoses between the umbilical arteries and veins. If, for any reason, the heart action of one of the embryos should become impaired, there would be an influx of blood into the vessels of that embryo owing to diminished pressure. Thus the blood from the stronger heart would be pumped into the affected embryo as well as into the placenta. This blood, being impure, fails to nourish the weaker embryo properly and the result is atrophy or degeneration.

Upon the basis of other malformations that naturally accompany impaired development of the heart, acardiac monsters are divided into four classes.

  1. Acardiacicompleti. The general development of the acardiacus depends upon the sufficiency of the blood supply which it receives. If there is a well developed anastomosis between the two placental circulations the weaker embryo may receive a moderately good blood supply and develop into a fairly normal foetus. A well formed trunk and head may be present and the extremities may be represented in part or in full.
  2. Acardiaci acormi. These may possess only a head, or they may possess a head and traces of a trunk and extremities. Their evolution depends upon unusual combinations of anastomoses in their venous channels.
  3. Acardiaci acephali. No head is present. The lower part of the trunk is present, and sometimes other parts of the trunk. The extremities may be complete, incomplete or absent. These forms are also due to peculiar combinations of vascular anastomoses.
  4. Acardiaci amor phi. As the name indicates, there is no typical form for the affected embryo. It bears no resemblance to a normal embryo, but is merely an irregular mass of tissue.

In symmetrical duplicity, instead of the two embryos in one chorion being distinct and separate individuals, they may be joined together to a greater or lesser extent. The two individuals may develop to practically the same degree (equal united twins,) or one may remain more or less rudimentary (unequal united twins.) As may be seen by reference to the scheme on page 605, there are three modes of union posterior, middle and anterior.

Posterior Union

This may be either dorsal or ventral. In dorsal posterior union the two bodies are joined together in the pelvic region, with the dorsal surfaces of the twins directed toward each other. The umbilicus is double and the two umbilical cords converge toward a common placenta pygopagus. The general anatomical features are as follows. There is a single coccyx and a single sacrum; pelvic bones and symphyses are present in normal number; near the ends of the large intestines the two digestive tubes unite to form a common lumen, and the two recta open through a common anus between the more dorsally situated pair of extremities; the two spinal cords unite near their lower ends to form a single conus and filum terminate; the urogenital tracts are united only to a slight degree. This form of monster is of interest because it is able to live for years; indeed a number of them have lived to maturity.

In case of ventral posterior union the attachment may be confined to the pelvic region or may involve the entire trunk. In the former instance ischiopagus the right pubic bone of one pelvis fuses with the left pubic bone of the other pelvis, the ventral surfaces of the two sacra facing each other. The axes of the bodies may be in line, or they may form an angle. The continuous ventral surfaces of the two bodies contain a. single umbilicus. The organs in the pelvic region may be single or double. The lower extremities may be fully developed, or there may be only three, or rarely two. Sometimes one of the twins is rudimentary, the thorax and head being absent, but the extremities present in part (ischiopagus parasiticus). Ischiopagi seldom survive owing to atresia of the anus.

In case the attachment extends along the entire trunk of each twin ischiothoracopagus the two sacra are usually fused to form a single sacrum. The thoraces of the twins are joined by means of a common sternum. The upper extremities may all be present (tetrabrachius), or there may be three (tribrachius), or only two (dibrachius) and a very rudimentary third. The lower extremities are subject to the same variations as the upper. The external genitalia and anus are single. The alimentary tube is double as far as the lower end. The thoracic viscera are partly double. Monsters of this type may live for years.

Middle Union

In the case of middle union a ventral or ventro-lateral attachment extends from the umbilicus for a variable distance toward the head. In most cases the umbilicus itself is single. The union may occur in the region of the xiphoid process xiphopagus or it may involve the entire region of the sternum sternopagus or thoracopagus. In the case of xiphopagus, a bridge joining the twins extends from the common umbilicus to the xiphoid processes. The latter are usually united across the bridge. The thoracic cavities are separate. The two livers may be connected by a bridge of hepatic tissue, in which case the two peritoneal cavities are in communication, or the livers may remain separate, in which case the peritoneal cavities do not communicate. The two alimentary tubes may or may not communicate in the region of the stomach. Xiphopagi may live for many years, as instanced by the "Siamese Twins."

In the case of sternopagus the union extends upward from the common umbilicus, so that the two sterna are fused into a single bone. There is a common thoracic cavity, separated from the abdominal cavity by a single diaphragm. One or two hearts may be present. The middle portions of the two alimentary tubes form a single tract. The two livers are fused into a common mass. The genitalia are distinct and separate. The extremities may be normal, or in case of a ventro-lateral union, the approximated upper extremities may be fused. Such monsters are usually born dead; if born alive, they survive but a short time owing to defective development of the heart.

As other varieties of thoracopagus the following may be mentioned : Thoracopagus parasiticus, in which one twin is much arrested in development, a head and heart being present, and attached to the thoracic region of the stronger twin. Gastrothoracopagus dipygus (dipygus parasiticus), in which extremities and trunk are present at least in part and are attached to the lower part of the thorax or to the epigastrium of the other twin. The head is not present. Such twins may live for years, as instanced by Laloo. Cephalothoracopagus diprosopus, in which the attachment may extend into the neck and head region, so that there is a union from the head to the umbilicus. This type is distinguished from the anterior union in that the head portions of the twins are united laterally, so that both more or less completely developed faces are turned toward the common ventral side, while the bodies have their ventral sides directed toward each other.

Anterior Union

In this type of union the attachment may be dorsal and confined to the head (dorsal anterior union), or ventral and reaching as far as the umbilicus (ventral anterior union).

In dorsal union the heads of the twins are joined at the crowns, so that the two bodies lie in a straight line, or form an angle with each other. Such a monstrosity is known as craniopagus (cephalopagus) . The attachment usually involves the cranial vault, the two brains remaining separated by their membranes within a common cranial cavity. Such monsters are rare and survive but a short time. A very rare variety of craniopagus is the form known as craniopagus parasiticus, in which one twin is reduced to a rudimentary structure and is parasitic upon the other. In all the above cases the term autosite is applied to the better developed twin.

In ventral and ventro-lateral union the attachment involves the head, neck and thorax syncephalus, cephalothoracopagus janiceps. The twins pass through their development in common, each individual contributing its quota of structure to the composite monster. The sternum is single, the oesophagus single, the larynx and trachea double or single, the stomach single, the intestine double. The two hearts may be united, but more commonly are separated, one being situated ventrally, the other dorsally. Two faces are formed, one belonging to each embryo. The faces may be alike or nearly so (Janus symmetros), or one may be misplaced or unequally developed (Janus asymmetros), which often results in cyclopia, synotia, or obliteration of the "opening of the mouth.

In some cases the greater part of the body is single and only a part is double (incomplete duplicity). The malformation may affect only the upper end or head (superior incomplete duplicity) , or only the lower end (inferior incomplete duplicity). In the former case the skull is single, with possible traces of a double formation diprosopus. There are two faces with varying degrees of fusion between them; all four eyes may be present, or the two approximated eyes may be fused or they may be wanting (diprosopus tetroph-, trioph-, diophthalmus). The two mouths may be fused (diprosopus monostomus), and with a greater degree of fusion between the faces the two approximated ears may .also be fused or be entirely lacking. In dicephalus the head is double, and sometimes the upper end of the vertebral column.

Inferior incomplete duplicity is rare. To this category of duplicate monsters probably belong certain cases of partial duplicity in the pelvic region, with sometimes an extra set of genitalia. Possibly also a few cases of a third lower extremity would come under this head.

Multiplicity

Monochorionic triplets are rare, only a few cases being recorded. Two cases of monochorionic quadruplets are on record, and one case of quintuplets. Incomplete multiplicities are extremely rare. One case of incomplete triplicity has been described tricephalus. Two vertebral columns were present in this monster, bearing one and two heads respectively. Two thoracic cavities, each enclosing a heart, were separated by a thin septum. The abdominal viscera were single. The lower half of the body and the lower extremities were normal, as were also the genital organs, which were male.

Origin of Symmetrical Duplicity

The origin of duplicities has always been most difficult to explain, and the many solutions suggested have been replete with conjecture. The difficulty has been caused by the lack of direct observation upon formative stages either in the lower or higher animals. Within recent years, however, experimental work upon the lower forms has begun to throw some light upon this obscure problem. Among the theories which have been formulated are two that stand out most clearly the fusion theory (Marchand, Ziegler) and the fission theory (Ahlfeld and others).

According to the fusion theory, there are present two originally distinct anlagen within a single ovum. These two anlagen may develop separately and independently and produce twins. They may come in contact during development and fuse to a greater or lesser degree, thus producing some kind of duplicate monster. If fusion does occur it occurs between similar parts of the two anlagen; in other words, like tissues and organs fuse liver with liver, muscle with muscle, bone with bone, and so on. Such unions, however, probably occur only in very early stages of development, for when tissues are once formed, union is effected with much greater difficulty. Consequently fusions between two anlagen, leading to double monsters, probably take place at a very early period of- intrauterine life.

According to the fission theory, duplicity is the result of the division of a single anlage in the earliest stages of development, before the formation of the primitive streak. The cleavage is produced by mechanical resistance of the zona pellucida. Since the greatest mass of growing material is in the head region, the resistance is greatest there, and hence it is argued that duplicities would be most common in the head region, which accords with the facts. A modification of the fission theory to explain duplicities which affect a relatively email area has been suggested. Incomplete anterior duplicity, for example, is not the result of fission but of bifurcation which accompanies the development of the head end of the embryo along divergent axes. The difference between fission and bifurcation is that the former is the passive result of active mechanical forces, while the latter is a part of active formative processes.

Experiments on eggs of lower animals point to the conclusion that each of the two blastomeres resulting from the first cleavage contains the material necessary to produce an entire body. In order to cause a blastomere to produce a whole body, however, it is necessary to subject it to unnatural conditions. For example, if one of the two primary blastomeres of the frog is killed and the other left to grow in its natural position it will produce a half-embryo; but if the remaining blastomere is inverted it will produce a whole embryo (Morgan). On the other hand, in view of certain experiments on the eggs of Amphioxus, it has been asserted that duplicity is associated with double gastrulation; when these eggs were shaken during the first cleavage, some developed into double gastrulae (Wilson, Hertwig). For a further discussion of these causes, see page 612.

Asymmetrical Duplicity

In this type of malformation the two anlagen from which the monster is derived are primarily dissimilar and unequal. One anlage usually remains in a rudimentary condition, bears little or no resemblance to a foetus, and becomes a parasite upon or within the body derived from the other anlage (parasite, foetal inclusion, foetus in fcetu). Sometimes, however, the dependent embryo may develop quite complete parts, such as extremities, but always remains attached to the stronger embryo, from which it derives its nourishment (implantation). Parasitic inclusions and implantations may be attached to the autosite in the region of the head, neck, thorax, abdomen, etc.

Parasitic duplicities in the head region may take the form of masses protruding from the orbital region prosopopagus parasiticus or much more commonly from the mouth epignathus, sphenopagus. In the latter case the tumor is enveloped by skin containing hair follicles and sweat glands, and usually consists of cysts and intervening embryonic tissue. It sometimes contains teeth, cartilage, bone, fat and nerve tissue, even traces of an intestinal canal and of liver tissue. One epignathus has been described as having an imperfect set of female genitalia which lay between two rudimentary lower extremities.

Occasionally irregular tumors are found in the region of the pituitary body (encranius), which contain rudiments of various tissues and organs. In such cases the parasitic anlage has possibly been included during the imagination which forms the oral part of the pituitary body. Tumors consisting of various tissues, such as lymphatic, adipose, muscle, etc., are also found in the. brain ventricles. They possibly represent parasitic anlagen which have become enclosed within the brain vesicles as the neural groove closed in dorsally.

Certain foetal inclusions attached to the region formed by the branchial arches are spoken of as cervical parasites. These are usually cystic tumors, covered with skin and containing teeth, bone and parts of a head and extremities.

Closely associated with the cervical parasites is a group of tumors found within the anterior mediastinum in the region of the thymus gland, and known as thoracic parasites. It must be borne in mind, however, that some of the tumors found in the cervical and thoracic regions are not true parasitic inclusions, but are dermoid cysts (resembling the parasites) derived from the ectoderm. True parasitism implies origin from all three germ layers. From a structural standpoint it is sometimes very difficult, even impossible, to distinguish between true parasitic inclusions and dermoid cysts that are derived from ectoderm.

Very rarely in the human subject some parasitic structure is attached to the back. One case of a supernumerary penis in the lumbar region has been described; another case is on record of an almost complete set of female genitalia on the back of a male. Such malformations can be explained only by assuming the partial development of another embryonic anlage.

"Sacral parasites are the most frequent of the true parastic growths. These are cystic tumors which are attached to and hang from the sacrum or the coccyx. The tumors are covered with skin which blends with the skin of the autosite. In the existence of such elements as fat, bone, muscle, and nerves, and the rudiments of intestines and extremities is found the evidence of their fcetal origin.

Foetal inclusions in the abdominal region are not frequent. One very rare intraparietal (or subcutaneous) inclusion, in a child two and one-half years old, proved to be a cystic tumor which contained a fairly well formed foetus with defective head and extremities. Engastric (intraabdominal) parasites are usually found in the region of the lesser peritoneal sac, at the root of the transverse mesocolon. These tumors are usually enclosed within a sac of mesenteric or peritoneal tissue. There may be well marked fcetal structures, such as head, trunk, extremities, etc., or only traces of rudimentary organsThe presence of an intraabdominal parasite does not necessarily cause the death of the autosite immediately after birth; for one case in particular is on record in which the autosite (a boy) lived to be fifteen years old with a parasite that was capable of independent movement.

Parasitic Structures in the Sexual Glands. The type of tumor referred to here forms a group that is of especial interest owing to their relative frequency of occurrence and to their peculiar mode of production. In connection with the ovary dermoid cysts and other solid masses occur. The cysts consist of a sac enclosing hair and adipose tissue; not infrequently teeth are also present, as well as sebaceous and sweat glands. Sometimes there are also bone, cartilage, muscle, and nerve tissue and traces of the digestive and respiratory systems and of thyreoid gland; more rarely traces of mammary glands, finger nails and retinal pigment are present. In the rarer solid tumors that develop in relation to the ovary all three germ layers are represented, but their derivatives are more rudimentary and not so regularly arranged as in the cysts.

Parasitic growths in the testis are much less frequent than in the ovary. The cysts are rarer than the solid masses. These are probably homologous with the parasites of the ovary.

Origin of Asymmetrical (Parasitical) Duplicity

Parasitic duplicity implies primary inequality of the embryonic anlagen; in other words, the anlage of the parasite is inferior, so to speak, to the anlage of the host. During development the inequality or asymmetry persists or becomes more conspicuous until the parasite is more or less enclosed within the autosite. As the autosite develops in a manner at least simulating the normal, the parasite remains in a more or less rudimentary condition, with perhaps only a few tissues which show any differentiation. In some cases the parasite becomes enclosed partially or completely within the autosite (epignathus), in other cases the parasitic growth apparently occurs primarily within the autosite (ovarian cysts).

The manner in which the rudimentary anlage becomes surrounded by the more nearly perfect anlage is, of course, not known through direct observation. But it seems reasonable to assume that such enveloping occurs in connection with or as a part of the normal processes of folding by which the external form of the body is established. This folding occurs at the cephalic and caudal poles of the embryonic disk and also along its entire length. In addition there is also the folding in of the neural groove along the dorsum of the embryo, and the invagination of the branchial grooves. One can readily imagine the parasitic anlage as attached to some one of the areas that are folded in, so that it is carried wholly or partially into the interior of the stronger embryonic anlage and becomes surrounded by the tissues of the autosite to produce a true foetal inclusion.

There seems to be little doubt as to the existence of a second, more or less rudimentary anlage which becomes the parasite; in other words, there is almost certainly a duplicity to begin with, although it may be an asymmetrical one. It is also plausible to assume that for a time the weaker anlage develops independently of the stronger, but that later it is dependent upon the stronger for its nutrition. The problem, however, is to explain the origin of the rudimentary anlage which produces the parasite. In view of the facts concerning the early stages of development the facts concerning maturation, fertilization and segmentation of the ovum, and the formation of the germ layers there are two possible and plausible modes of origin of the rudimentary anlage. (i) The anlage of the parasite may be the result of the imperfect development of a fertilized polar body. (2) The anlage of the parasite may be a special or an isolated group of segmentation cells.

1. It is generally agreed that the polar bodies are abortive or rudimentary ova extruded during the processes of maturation of the female sex cell; and that these rudimentary ova probably contain the same morphological constituents as the mature ovum itself. It is also known that in a few of the lower forms the polar bodies are capable of being fertilized and undergoing a considerable degree of development, and that in some of the higher forms (rabbit, dog) the spermatozoa may exist for some time inside the zona pellucida in the vicinity of the polar bodies. In view of these facts it does not seem impossible that in a few exceptional cases in Mammals the polar bodies may become fertilized and produce rudimentary anlagen capable of giving rise to parasites. Such an anlage would naturally lie in close proximity to the larger normal anlage and might readily become attached to or finally enclosed within it. As a more remote possibility, the polar body might become enclosed between the blastomeres and thus finally produce the parasitic anlage within the mesodermal tissue where it might become an inclusion in some internal organ, such as the genital gland. A polar body has been found between the blastomeres (rabbit). (Bischoff, Assheton, Bonnet.)

2. The view that the parasite may arise as the result of the development of a special or an isolated group of segmentation cells has more advocates than the view given in the preceding paragraph. One of the most interesting phases of this theory is the view that tumors of the sexual glands, as well as those of other regions, are the products of development of the germ cells as distinguished from the somatic cells. In the skate it has been demonstrated that certain cells are set apart at a very early period of development (during segmentation), which are destined to give rise to the sex cells of the embryo, and which take no part in its general development. Normally these special cells pursue a course of development and differentiation which leads to the formation of the mature sexual elements (ova or spermatozoa) of the individual, but do not participate in its general development. From this one may conclude that the primitive germ cell, the one set apart for the production of the mature sex cells, is, so to speak, a sister to the embryo and is not a derivative of the embryo. It seems not impossible that some aberrant members of this group of germ cells, without undergoing the changes incident to maturation, might pursue a course of development of their own accord and give rise to a rudimentary twin the foetal inclusion or parasite. In this case one must regard the germ cells as possessing an inherent potentiality which may institute formative processes; but the actual cause of the spontaneous development is unexplained. (Born, Wilson, Morgan, Driesch, Schultze).

Another possible source of parasitic growths is suggested by experiments in which some of the cells during segmentation have been separated from the general mass. The artificially segregated cells may develop into perfect embryos smaller than the normal, or into partial embryos. Further experiments along the same line on the frog justify the assumption that the segregated cells or masses may become enclosed within the developing larger embryo and there undergo further growth and differentiation and give rise to inclusions or parasites. (Roux.)

As a matter of fact there seems to be no good reason for considering any one of the above views as expressing the only possibility as to the source of unequal duplicities or parasitic growths. There is nothing to show that all three methods may not contribute to the various kinds of duplicities including certain teratomata of the sexual glands.

Malformations Involving One Individual

Description, Origin.

While the more limited malformations and anomalies affecting individual organs are discussed in the chapters dealing with those organs, it seems best to consider here some of the gross malformations in a single individual, especially those which affect the external form of the body.

Defects in the Region of the Neural Tube

The term cranioschisis has been given to a group of malformations, or defects, in the roof of the skull and in the brain. Depending upon the degree of defect, the group is divided into two classes acrania and hemicrania which include conditions from a complete absence of the roof of the skull to partial arrest of development. Associated with these conditions are varied defects and malpositions of parts or of the whole of the brain.

In extensive acrania the entire roof of the skull is lacking, and the brain and its membranes are reduced to small masses of tissue lying upon the floor of the skull. The defect may also extend to the cervical vertebrae craniorachischisis. These vertebras remain open dorsally and are bent inward (lordosis). The ears are set upon the shoulders and the neck seems to be lacking.

Sometimes the rudimentary brain shows traces of structures which the normal brain possesses, and is raised above the level of the defective skull like a turban acrania with exencephaly. With acrania are usually associated facial clefts, defects in the eyes, etc.

The malformation known as hemicrania is limited to a part of the skull, usually the posterior part. The brain mass often protrudes through an opening in the cranial vault and forms a mass on the back of the head or hanging down upon the neck hemicrania with exencephaly.

In the various forms of cephalocele or cerebral hernia the roof of the skull is more nearly complete and the protrusion of the cranial contents is limited to circumscribed areas. The protruding mass may consist of brain substance only encephalocele, or of the membranes only meningocele, or of both meningoencephalocele. Sometimes the brain ventricles are distended by the accumulation of fluid hydrencephalocele, or a sac formed by the membranes may be distended by fluid hydromeningocele.

A condition known as hydrencephaly is sometimes met with. Fluid accumulates in the brain cavities after the skull is formed, causing a general enlargement of both brain and skull, without hernia (congenital hydrocephaly) .

A combination of hydrencephaly and cephalocele may also occur. The cervical vertebrae adjoining the skull are cleft dorsally and the protruding mass lies in the cleft iniencephaly.

Hydromicrencephaly means an accumulation of fluid with a rudimentary brain and a correspondingly small skull.

Porencephaly is a lower grade of hydromicrencephaly, in which fluid accumulates in the third and lateral ventricles and affects the adjacent frontal and parietal lobes. If the individual lives with this malformation, the intellect is impaired and the extremities contract and atrophy. .

Microcephaly and micrencephaly go together as abnormal smallness of the skull and brain. The brain, aside from the diminutive size, may not be deformed. These conditions, in which the body is of the usual size, should not be confused with those found in dwarfs in whom the body also is small (nanocephaly) .

In the region of the spinal cord there is a group of malformations consisting of varying degrees of clefts in the vertebral canal. The clefts may remain open rachischisis or they may be covered by a sac-like prominence spina bifida (spina bifida cystica, rachischisis cystica). Both forms of cleft may occur in any region of the vertebral column and may be limited, or involve the entire column.

The malformation known as rachischisis appears as a widely open groove bounded laterally by rudimentary laminae of the vertebrae. The deformity may include the entire vertebral column holorachischisis, or it may be confined to a small part merorachischisis, and is usually accompanied by curvature of the spine. Sometimes the deformity of the vertebral column is continuous with cranioschisis craniorachischisis. The more or less rudimentary spinal cord lies along the bottom of the cleft. When the rachischisis is total the spinal cord is practically wanting amyelus.

Spina bifida is marked by the presence of a cyst which protrudes through a cleft in the vertebral column; externally it presents the appearance of a saclike structure of variable size. Three different types of spina bifida may be recognized, depending upon the structures involved. If the cord and its membranes are included in the cyst it is known as myelomeningocele; if only the membranes, as spinal meningocele; if the cord itself is dilated, as myelocystocele.

Myelomeningocele is the most common form of spina bifida and usually occurs in the lumbo-sacral region, rarely in the cervical or thoracic region. Its appearance is that of a rounded tumor in the medial line, and, if the child lives, the tumor increases in size and may become as large as a child's head. The spinal cord is bent dorsally and attached to the sac. The pia mater and arachnoid surround the cord, while the dura is incomplete. The spinous processes and the adjacent parts of the arches of the vertebrae are absent. From one to several vertebrae may be affected.

In spinal meningocele the spinal membranes bulge out to form a sac filled with fluid. The vertebrae are not necessarily defective, for the sac may protrude between the arches or through the intervertebral foramina; it more often protrudes laterally than dorsally. The presence of meningocele is not at all incompatible with life, but the sac usually enlarges to a good-sized tumor.

In myelocystecele (syringomyelocele) the central canal of the spinal cord is dilated locally, with the result that a portion of the cord with the pia and arachnoid becomes a cystic tumor. It may occur in any region, and is frequently associated with asymmetrical defects of the vertebral column.

Spina bifida occulta, a condition in which neither cleft nor tumor is visible externally, is usually found in the lumbo-sacral region. The position of the defect is indicated by a small depressed cicatrix or by a small tuft of hair. The spinal cord is elongated and extends into the sacral canal. The spinal canal is sometimes dilated and the cauda equina affected, in consequence of which there are sensory and motor disturbances in the lower extremities. Paralytic club-foot and derangement of the bladder functions may result from such a deformity of the cord.

Diastematomyelia, or doubling of the spinal cord, sometimes accompanies rachischisis. The cord in such cases is represented by two atrophic bands.


Teratogenesis Origin of Malformations in the Region of the Neural Tube

Normally the neural tube is formed from a band of ectoderm extending along the dorsum of the embryonic disk. The ectodermal band becomes thickened, a groove appears along the middle line and the margins are raised above the surface of the embryo, forming the neural groove. The margins of the band continue to push upward and finally meet and fuse with each other throughout their entire length in the middorsal line. The surface ectoderm then breaks away from the line of fusion and forms a continuous layer upon the dorsum of the embryo, thus leaving the neural groove, now the neural tube, extending the entire length of the embryo immediately beneath the ectoderm.

The formation of the neural tube is a fundamental process, occurring at an early period. It is obvious that any interference with its development will be followed by serious defects in the nervous system and the structures that immediately surround it. A most natural result of such interference would be the failure of the two margins of the neural groove to unite, and it is not improbable that the various forms of cranioschisis are the results of imperfect or complete lack of closure of the cephalic end of the neural groove. Such failure of the neural groove to close would leave the dorsum of the head region open, so that not only the brain but also the cranial vault would be affected. If the failure to close is complete, a high degree of acrania would result. In case of partial closure some form of hemicrania might follow.

Rachischisis, with partial or total absence of the spinal cord, may also be attributed to defective closure of the neural tube, total rachischisis being due to complete lack of closure, partial rachischisis to partial lack of closure.

The origin of spina bifida has been a much discussed question. The earlier view that the deformity was due to accumulation of fluid within the spinal canal and rupture of the distended sac is now usually considered untenable. At the present time it is generally agreed that spina bifida is closely related to defective closure of the neural tube, although the exact nature of this relation is not known.

According to one investigator the defective fusion of the margins of the neural groove is due to deficient growth of the blastoderm (von Recklinghausen). Another view is that the separation between the neural tube and the adjacent ectoderm is incomplete (Torneux). Still another investigator considers the defective development due to some primary defect in the germ (Ziegler). Experimental studies on the frog's egg suggest to another observer that spina bifida is caused by defective closure of the blastopore (Hertwig). Recently it has become possible to produce spina bifida at will in some of the lower Vertebrates (frog, Axolotl) by treating the developing eggs with a solution of sodium chlorid (Hertwig). At the same time other defects in the nervous system (anencephaly) are produced. In these experiments the malformations follow retarded closure or lack of closure of the neural tube.

Defects in the Region of the Face and Neck, and their Origin

Associated with malformations of the brain there is a group of defects which involye the eyes and nose, and to which the term cyclocephaly has been applied. The cerebral hemispheres are derivatives of the fore-brain. Sometimes they fail to develop properly and are represented by a single mass occupying a considerable portion of the cranial cavity. The eyes primarily represent lateral, symmetrical outgrowths from the fore-brain vesicle. If the cerebral hemispheres fail to develop, the development of the eyes is profoundly influenced. Instead of being widely separated there may be any degree of malformation from a mere narrowing of the distance between them to a complete fusion into a single organ within a single medial orbit synophthalmia or cyclopia. Within this orbit the eye may possess double or partially blended corneae, pupils, lenses, and optic nerves, or it may have single structures.

Since the fronto-nasal process, which plays an important part in the formation of the nose, depends for its normal shape upon the development of the forebrain region, various degrees of malformation of the nose almost invariably accompany cyclopia. In a typical cyclops the nose is reduced to a fleshy mass protruding from the frontal region.

It is not unusual to find clefts of the upper lip (hare lip) and of the palate (cleft palate) associated with cyclopia; for the normal union of the frontonasal and maxillary processes depends upon the development of the fore-brain region. The branchial arches likewise may be affected with resulting malformations of the mouth and external ear. The two ears may be united across the ventro-medial line synotus or cyclotus, and the mouth slit may be absent cydostomus.

The eye may also be the seat of local defects. It may remain abnormally small micf 'ophthalmia, or incompletely developed, or may be entirely lacking anophthalmia. The eyelids . may enclose an abnormally narrow fissure ankyloblepharon, or the fissure may be wanting cryptophthalmia, or the lids may be adherent to the eyeball symblepharon. Sometimes there is a cutaneous fold which partly fills the inner canthus like the nictitating membrane in lower forms epicanthus.

Malformations of the face are not uncommon, all such congenital defects being due to incomplete fusion of the processes which form the jaws and greater part of the face (see page 1 20) . In extreme cases there is an early and complete arrest of development of all the parts which normally form the face aprosopus. Arrested development of the first pair of branchial arches results in abnormally small lower jaws micrognathy, or in almost complete absence of the lower jaws agnathus; in the latter case the ears are brought together in the ventro-medial line synotus. Rarely the mandible is partly duplicated, due to the development of a secondary mandibmar process dignathus.

Clefts in the upper lip, maxilla and palate follow the lines of primary union of the processes which form these structures (consult Figs. 98 and 99) . The cleft may affect the lip alone, may be single or double, but is always lateral hare lip (cheiloschisis). It may affect the *.p and maxilla (cheilognathoschisis), or the lip, maxilla and palate (hare lip and cleft palate, cheilognathouranoschisis). (For a further discussion of hare lip and cleft palate, see p. 180).

Occasionally there is an entire lack of union between the naso-frontal process an$ the maxillary process. The result is an oblique cleft which extends upward from the mouth oblique facial cleft (cheilognathoprosoposchisis) . The processes which form the boundaries of the mouth slit (maxillary and mandibular processes) sometimes fail to fuse to the normal extent, thus giving rise to macrostomus; or the fusion may proceed beyond the normal limit, giving rise to microstomus; rarely complete fusion of the processes on one side with each other and with their fellows of the opposite side results in closure of the mouth slit astomus or atresia oris. Clefts in the lower lip, due to imperfect union of the two mandibular processes in the medial line, are rare.

The branchial arches (apart from the first which has already been considered) and the branchial grooves are also subject to defective developmental processes. Malformations of the ear, with closure of the external auditory meatus, due to abnormal development of the first groove and surrounding parts, are sometimes met with either alone or in connection with other facial defects. Cervical fistula are the results of imperfect closure of some of the grooves along with rupture of the membranes that separate the bottoms of the external grooves from the bottoms of the internal grooves or pharyngeal pouches. The fistula may be complete, that is, there may be a communication between the pharyngeal cavity and the exterior; or it may be incomplete, opening either into the pharynx, or on the surface of the body. The internal opening of a cervical -fistula is usually in the lower part of the pharynx or in the posterior palatine arch near the tonsil. The external opening varies in position. It is usually situated near the sterno-clavicular articulation, or at the inner or outer edge of the sterno-mastoid muscle. The majority of cervical fistulae are probably derived from the second branchial groove. They all have the form of narrow canals lined with mucous membrane. Medial cervical fistulae, the external openings of which are situated in the medial line, are rare.

It sometimes happens that during the closure of the branchial grooves portions of the walls of the grooves becomes enclosed within the walls of the pharynx, that is, within the sides of the neck. This abnormal process results in various forms of cysts and tumors. The most common are simple retention cysts, known as branchial or branchio genetic cysts, which vary from small insignificant structures to large tumors. If derived from the external branchial furrows, they are dermoid in character, lined with ectodermal derivatives, and contain sebaceous material. If derived from the internal furrows, they contain mucous fluid, the lining epithelium is likely to be columnar and is claimed by some to be ciliated.

DEFECTS IN THE THORACIC AND ABDOMINAL REGIONS, AND THEIR ORIGIN

As described elsewhere (see page 285), the digestive tube (primitive gut) and ventral body wall are formed primarily by a bending ventrally and fusing of the originally flat germ layers. The splanchnopleure on each side first bends ventrally and fuses with its fellow of the opposite side in the medial line to form the gut, and soon afterward the somatopleure likewise fuses in the ventromedial line to form the body wall. Naturally a defective fusion of the two sides of the somatopleure would result in a more or less extensive medial cleft. The cleft may be limited to a small portion of the abdomen or thorax, or may extend from the neck to the pelvis.

When the cleft is very extensive and involves the thoracic and abdominal walls, the condition is known as thoracogastroschisis. In this case most of the viscera protrude through the cleft (ectopia viscerum) and are covered merely by peritoneum. Spinal curvature of a low or high degree is usually associated with the eventration.

The cleft may involve the entire abdominal wall gastroschisis completa and the abdominal viscera may protrude through it. In a somewhat lesser degree of fission, parts of the abdominal viscera, covered with peritoneum, may protrude and form what is known as omphalocele. Not uncommonly portions of the intestine and omentum protrude through an abnormally large umbilical ring umbilical hernia. The region below the umbilicus is not infrequently the seat of fissures in the abdominal wall, through which the bladder may protrude (ectopia vesicae) . Fissures in the thoracic wall vary in extent. When the defect is extensive the heart and pericardium protrude through the opening (ectopia cordis).

Malformations of the Extremities

Any degree of deficiency may exist, from total absence of extremities to the lack of a single finger. The malformations, however, are not confined to total or partial lack of members, for supernumerary fingers and toes are sometimes present. The following is the classification given by Piersol:

1. One or More Extremities Wanting. (a) Amelus. Both upper and lower extremities are practically absent, (b) Abrachius, A pus. Either the upper or lower extremities are wanting, the other pair often being well formed, (c) Monobrachius, Monopus. One upper or one lower extremity is absent, the others being fully developed.

2. One or More Extremities Defective. (a) Peromelus. All the extremities are imperfect. A striking variety of this is the suppression of the proximal segments of the extremities, the hands and feet being fairly well formed (phocomelus). (b) Perobrachius, Peropus. The former signifies defective development- of the upper, the latter of the lower extremities.

3. One or More Extremities Abnormally Small but well Formed. (a) Micromelus. All the extremities are diminutive, but without any other malformation, (b) Microbrachius, Micropus. One or both upper extremities may be small, or one or both lower.

4. Bones Defective or Absent. Such malformations are rare.

5. Lower Extremities Fused. (a) Sympus (symelus siren). The lower extremities are fused more or less completely, and the lower end of the trunk is abnormal. The feet may be imperfect and double (sympus dipus), or a single foot may be present (sympus monopus), or the feet may be wanting (sympus apus) .

6. Hands or Feet Defective. There is a great variety of malformations of the hands and feet due to arrested development of some of the digits. The variations include all degrees of suppression from the shortening of a finger or toe to almost total absence of digits. Fusions of two or more digits are not uncommon. Occasionally a structure, suggesting the webs on the feet of some aquatic animals, is present.

The condition known as polydactyly (an increase over the normal number of digits) is occasionally met with. The increase may range from a partial doubling of the distal segment of a finger or toe to a two-fold quota of digits. Cases of ten digits are extremely rare, as are even cases of seven or eight. One supernumerary finger or toe, rudimentary or complete, is not uncommon. The extra digits may appear on a single hand or foot, or on both hands or feet, or on all four extremities, not necessarily showing any symmetry. A statement of the possible modes of origin of polydactyly will be found on page 181.

Amniotic Adhesions

Many malformations affecting the embryo or foetus have been included under this head. It has been generally thought that the amnion might become attached to some part of the embryo in such a way as to cause malformations by interfering with the normal processes of ^growth. The amnion might become attached to the head and by interfering with normal growth produce hare lip, facial clefts and generally serious disturbances. Undue pressure on an extremity would cause it to be stunted, or an encircling band of amniotic tissue might cause constriction or even ampu^ tation of some of the extremities, or of some of the digits. Under the same -head there might also be included certain disturbances possibly caused by the umbilical cord. The cord by becoming wound around the neck or extremities and interfering with development may even cause the death of the foetus.

Causes Underlying the Origin of Monsters

Within the past century the old grotesque notions that monsters were the results of supernatural influences or of sexual congress with lower animals have been overthrown as teratology has been placed upon an embryological basis. The very old belief that impressions on the maternal senses may influence the development of the embryo is still held by those who possess little or no scientific knowledge, and is not uncommon even among gynecologists and obstetricians. While remarkable cases of coincidence have been recorded, there seems to be no proof whatever that maternal impressions are reflected upon the child in the uterus. On the other hand, there has gradually accumulated a large amount of negative evidence obtained from experimental work. The results of this work have been such as to indicate that external influences mechanical or physico-chemical cause the production of monsters.

Opposed to the theory that monsters are due to external influences is the view that their cause lies within the germ, that is, that some inherent defect in the constitution of one or both of the parental germ cells is brought out in the new organism that develops after their union. According to this theory, therefore, heredity is the important factor in teratogensis. While the occurrence of defective conditions in the germ cells cannot be demonstrated, the apparent influence of heredity in the production of malformations has long been recognized. Certain malformations, even so great as to put the embryo or fcetus in the class of monsters, have been known to occur in families through successive generations. Such cases may be mere coincidences, yet more probably they are indicative of hereditary influence.

All the theories, therefore, are concerned with the question "whether the conditions that produce a monster are germinal and hereditary or are external influences acting upon a normal germ" (Mall). Some defend the germinal or hereditary factor as the most potent cause in the production of malformations, while others just as strongly advocate the view that normal or abnormal development depends largely upon external factors. It does not seem possible to deny the importance of heredity in the development of the normal organism; nor, on the other hand, can the importance of external influence, of environment, upon normal development be denied. The same factors may be considered as active in abnormal development, and it does not seem that either factor can reasonably be considered as the only cause in the production of malformations. Granting, however, that both hereditary and external influences are at work in the production of monsters, it is still difficult to determine the separate role of each factor; on the one hand, either influence may appear capable of having produced some given anomaly; on the other, both of them may have been responsible for its appearance.

The first phase of the theory of external influence was presented threequarters of a century ago when attempts were made to produce monsters. The experiments led to the formulation of the mechanical theory, which, when applied to human monsters, considers them as the results of mechanical influences upon the embryo, such as the pressure caused by tight lacing or by contractions of the uterus. This theory was gradually transformed into the view that amniotic bands compress or constrict the embryo, thus bringing about malformations. In its turn the latter supposition has recently been criticized and the view substituted that the amniotic adhesions are the results of malformations and not the cause of them (Mall).

The theory of external influence seems recently to be losing ground in favor of the physico-chemical theory. The latter has gradually been evolved during the course of a great number of experiments on the production of malformations and monsters among the lower forms of animals. It has gained ground because certain definite malformations have been obtained by subjecting the living egg or young embryo to unusual conditions. The experiments consist of interfering in some way with the normal course of development. The interference may be mechanical or chemical, or both, but is always of such a nature as to cause the egg or embryo to develop under unnatural conditions either in an unnatural environment or after having had some of its own substance wholly or partly removed. The results obtained, the strange creatures which develop after such interference, are not infrequently comparable with malformations and monsters found among the higher animals, and they strongly suggest that malformations among the higher forms of animal life are the results of similar interference with the normal course of development of the egg.

THE PRODUCTION OF DUPLICATE (OR POLYSOMATOUS) MONSTERS

By shaking sea-urchin ova when in the two-cell stage so that the blastomeres are separated, each blastomere can be made to grow into a whole embryo. Depending upon the degree of separation, the two embryos will be separate or more or less united forming a double monster. If sea-urchin ova are placed in a mixture of equal parts sea-water and distilled water shortly after fertilization, the cell membranes rupture and part of the protoplasm bulges out. When the ova are replaced in normal sea-water cleavage begins and one of the two primary nuclei wanders into the extruded protoplasm. Each nucleus with its protoplasm becomes an embryo, and the result is a double monster. If the outflow of protoplasm originally occured in several places, each droplet produces an embryo and the result is a triple or quadruple monster (Loeb).

Similar experiments have also been performed on Vertebrates. For example, the two primary blastomeres of Amphioxus have been partly separated and double monsters developed. The blastomeres in the four-cell stage have been incompletely separated, resulting in double embryos of equal size, or triple embryos, or quadruple monsters. Frog's eggs have been made to produce double monsters by keeping them turned upside down after the morula stage; the same result has also been produced by loosely tying a ligature in the furrow between the two primary blastomeres. A most curious result has been obtained by splitting the limb bud of a growing tadpole one or more times. Two or even a cluster of limbs may develop where only one does normally (Tornier).

These few examples from the great number of experiments which have been performed serve to show that great light can be thrown upon the problems of teratogenesis by experimental embryology. While they do not prove that there are no other possible modes of origin for malformations, they indicate the importance of external influences upon development, and afford tangible evidence in the study of monsters.

THE PRODUCTION OF MONSTERS IN SINGLE EMBRYOS

In single embryos of the lower forms it is possible to produce by various means a great variety of malformations, many of which are likewise comparable with malformations found in human embryos. By placing recently fertilized eggs of Fundulus in a 1.5 per cent, aqueous solution of potassium chlorid, embryos may be produced in which the heart is developed but does not beat, and in which the blood vessels appear in their normal positions but with irregular lumina (Loeb). After extirpating the heart anlage from very young frog embryos, the latter grow irregularly and become edematous; the larger vascular trunks are distended, but the capillary system is imperfect or absent, and the development of ninny other organs is inhibited (Knower.) Similar results may be obtained by placing the young embryos in aceton-chloroform which inhibits the heart action.

It is possible to produce typical spina bifida in frog embryos by putting them, during the early stages of development, into a 0.6 per cent, solution of sodium chlorid (Morgan and Tsuda). If the eggs of Axolotl are treated with a 0.7 per cent, solution of sodium chlorid all the embryos have spina bifida (Hertwig). If the eggs of Fundulus are placed in a solution of magnesium chlorid, 50 per cent, of them produce embryos with cyclopia (Stockard).

Even these few examples from the enormous number of experiments that have been tried in the study of single monsters again lead to the conclusion that at least some malformations in single individuals are due to external influences and not to germinal defects.


THE SIGNIFICANCE OF THE FOREGOING IN EXPLAINING THE PRODUCTION OF HUMAN MONSTERS

There is, of course, no way to obtain experimental evidence for or against any theory so far as the human subject is concerned. But it is possible to compare the results of experiments on the lower animals with condions found in human embryos. So many malformed human embryos resemble in a general way and often in detail the monsters in the lower forms produced by experimental means that a probable similarity in the causation of them at once suggests itself. The monsters in the lower forms are artificially produced by interfering with the normal course of development of the egg, and by disturbing the normal conditions of nutrition and growth. The disturbing factors are mechanical or chemical, or both.

According to the recent opinion of Mall, the primary disturbing factors in man are not poisons in the maternal blood, corresponding with chemical agents used in experiments, but the faulty implantation of the ovum in the uterine mucosa. This means that, after the fertilized and segmenting ovum has passed down the oviduct and entered the uterus, it fails to become properly embedded in the mucous membrane. The immediate result is an imperfect formation of the foetal coverings, especially of the chorion.

The reasons for the faulty implantation are not clear, but they are possibly, even probably, to be found in the condition of the uterus. The most plausible explanation is that some form of endometritis makes the uterine mucosa incapable of properly adapting itself for the reception of the ovum.

In the case of the human embryo, such an imperfection in the agency through which it receives its nourishment might be considered in a sense analogous to the external influences that produce monsters in the lower forms.

Recognizing the fact that a given animal passes through its embryonic stages at a specific rate of development, which is probably dependent upon the rate of oxidation in the protoplasm, Stockard has conducted an extensive series of experiments on animals (Fundulus, or sea-minnow) and analyzed the results with the view of throwing light upon the probable causes of malformations and monsters. His experiments comprised the interruption or slowing of the rate of embryonic development either by temporarily lowering the surrounding temperature and thereby reducing the rate of oxidation in the protoplasm or by cutting off the supply of oxygen. When the temperature of the eggs during the cleavage stages was reduced for a time to 5 or 6 Centigrade and then raised to normal it was found that in later development a significant percentage of twins and a number of malformations appeared. Similar results were obtained by directly reducing the supply of oxygen. When exposed to such experimental conditions in later stages of development, the eggs did not produce duplicate monsters. There seemed to be a critical stage at which it was necessary to apply the experimental conditions in order to produce certain types of malformations. From this it was inferred that the results of inhibiting the rate of development depend upon the developmental moment at which the interruption occurred. These and other results obtained by Stockard led him to the conclusion that changes in the conditions of temperature and oxygen supply are the most frequent causes of abnormal and monstrous development and embryonic death. In the mammals, with their relatively constant temperature, the developmental environment is under natural control, but it is not always perfectly regulated. This lack of perfect regulation causes disturbances in the oxygen supply which are regarded as potent factors in the production of malformations and monsters.

A significant fact relative to inhibition of development is found in the normal production of quadruple offspring of the nine-banded armadillo. In this animal the egg undergoes the early developmental stages up to blastocyst formation while it is traversing the oviduct. When it reaches the uterus the blastocyst lies in the lumen for about three weeks before it becomes embedded in the uterine mucosa. During this period development practically ceases, and the logical cause of the stoppage is the lack of oxygen. Then when implantation occurs development sets in again and the blastoderm divides into four embryonic rudiments which give rise to the four offspring.

As stated above, Mall attributed the production of monsters and malformations to faulty implantation of the ovum in the uterine mucosa with the resulting disturbances in the nutritional relations of the developing embryo. Stockard has added in this connection the specific factor of disturbance in the oxygen supply.


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References for Further Study

AHLFELD, F.: Die Missbildungen des Menschen. Leipzig, 1880-1882.

AHLFELD, F.: Lehrbuch der Geburtshilfe. Leipzig, 1903.

BALLANTYNE, J. W.: Antenatal Pathology. 2 Vols. Edinburgh, 1904.

BARDEEN, C. R.: Abnormal Development of Toad Ova Fertilized by Spermatozoa exposed to the Roentgen Rays. Jour, of Exp. ZooL, Vol. IV, 1907.

BEARD, J.: The Morphological Continuity of the Germ Cells in Raja batis. Anat. Am., Bd. XVIII, 1900.

CONKLIN, E. G.: The Cause of Inverse Symmetry. Anat. Aw., Bd. XXIII, 1903.

DARESTE, C.: Recherches sur la production des monstrosites. Paris, 1891.

DRIESCH, H.: Entwickelungsmechanische Studien. Zeitschr. f. wissensch. ZooL, Bd. LIII, Bd. LV.

FORSTER: Die Missbildungen des Menschen. Jena, 1865.

GUDERNATSCH, J. F. : Hermaphroditismus vera in Man. Am, Jour, of Anat., Vol. XI, 1911.

HERTWIG, O.: Urmund und Spina bifida. Arch. f. mik. Anat., Bd. XXXIX, 1892.


HERTWIG, O. : Die Entwickelung des Froscheies unter dem Einfluss schwacherer und starkerer Kochsalzlosungen. Arch. f. Mik. Anal., Ed. XLIV, 1895.

HERTWIG, O.: Missbildungen und Mehrfachbildungen. In Hertwig's Handbuch der vergleich. u. experiment. Entwickelungslehre der Wirbeltiere, Bd. I, Teil I, 1903.

HIRST and PIERSOL: Human Monsters. Philadelphia, 1891.

KNOWER, H. McE.: Effects of Early Removal of the Heart and Arrest of the Circulation on the Development of Frog Embryos. Anat. Record, Vol. VII, 1907.

LOEB, J.: Beitrage zur Entwickelungsmechanik der aus einem Ei entstehenden Doppelbildungen. Roux's Arch. f. Entwickelungsmechanik der Organismen, Bd. I, 1895.

LOEB, J.: Studies in General Physiology. Chicago, 1905.

MALL, F. P.: A Study of the Causes Underlying the Origin of Human Monsters. Jour, of Morphol., Vol. XIX, 1908.

MALL, F. P.: On the Frequency of Localized Anomalies in Human Embryos and Infants at Birth. Am. Jour, of Anat., Vol. XXII, 1917.

MARCHAND, L.: Missbildungen. In Eulenburg's Real-Encyclopadie der gesammten Heilkunde, Bd. XV, 1897.

MORGAN, T. H.: Half-embryos and whole Embryos from one of the first two Blastomeres of the Frog's Egg. Anat. Am., Bd. X, 1895.

MORGAN, T. H.: Ten Studies in Roux's Arch. f. Entwickelungsmechanik der Organismen, Bd. XV-XIX, 1902-1905.

NEWMAN, H. H. : The Biology of Twins. 1917.

PANUM: Entstehung der Missbildungen. Berlin, 1880.

PIERSOL, G. A.: Teratology. In Wood's Reference Handbook of the Medical Sciences, Vol. VII, 1904.

SCHULTZE, O.: Die kunstliche Erzeugung von Doppelbildungen bei Froschlarven mit Hilfe abnormer Gravitationswirkung. Roux's Arch. f. Entwickelungsmechanik der Organismen, Bd. I, 1895.

SCHWALBE, E.: Die Morphologic der Missbildungen des Menschen und der Thiere. Jena, 1906-1907.

STOCKARD, C. R.: The Artificial Reproduction of a Single Median Cyclopean Eye in the Fish Embryo by Means of Sea- water Solutions of Magnesium Chlorid. Roux's Arch. f. Entwickelungsmechanik der Organismen, Bd. XXIII, 1907!

STOCKARD, C. R.: Developmental Rate and Structural Expression: An Experimental Study of Twins, " Double Monsters " and Single Deformities, and the Interaction among Embryonic Organs during their Origin and Development. Am. Jour, of Anat., Vol. XXVIII, No. 2, 1921.

TORNIER, G.: An Knoblauchskroten experimentell entstandene uberzahhge Hmter gliedmassen. Roux's Archf. Entwickelungsmechanik der Organismen, Bd. XX, 1905.

WILDER, H. H.: Duplicate Twins and Double Monsters. American Jour, of Anat.,

Vol. Ill, 1904.

WILLIAMS, J. W.: Obstetrics. New York, 1903.

WILSON, E. B.: On Multiple and Partial Development in Amphioxus. Anat. Aw., Bd. VII, 1893.



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