Human Congenital Malformations Research Articles

Congenital Malformations of the External Middle, and Inner Ear Produced by Isotretinoin Exposure in Mouse Embryos

Isotretinoin (Accutane), a widely used dermatologic drug, produces severe congenital malformations when used during pregnancy. The isotretinoin teratogen syndrome consists of multiple cardiovascular and craniofacial anomalies, most commonly involving the external ear. This study examined the pathogenesis of isotretinoin teratogenicity in a mouse model, using microdissection and histologic examination of fetal mouse ears after treatment with the drug at various stages of embryonic development. In this study, earlier treatment times frequently produced microtia similar to that seen in affected infants, as well as recognizable patterns of temporal bone and ossicular abnormalities; exposure at a later developmental stage resulted in facial tags with less severely affected ears. Possible teratogenic mechanisms of isotretinoin are discussed. Suitability of the mouse model for studying human congenital craniofacial malformations, such as Goldenhar's and Treacher Collins Syndrome, is also explored.

Epidemiological Approaches to Identify Risk Factors for Human Congenital Malformations: Descriptive and Analytical Epidemiology of Cleft Lip and/or Palate in Japan*

Abstract This paper described three major epidemiological approaches to explore etiological clues to and risk factors for human congenital malformations, taking cleft lip and/or palate as an example. (1) An analysis of mortality statistics demonstrated an apparently downward trend of infant mortality from cleft lip and/or palate over the recent three decades in Japan. This particular finding was found to be plausibly ascribable to changing clinical assignment of causes of death from “cleft lip and/or palate” to “congenital heart diseases” or “multiple anomalies, syndromes or chromosome abnormalities”, when previous reports on incidence rate and autopsy series were examined. (2) A case‐control study of 194 infants with cleft lip and/or palate (cases) and 194 normal infants (controls), who were matched to cases for sex, maternal age to within one year, birth order and residential area, yielded the following major findings, (a) A significantly increased risk was associated with parental highest educational attainment of less than 19 years, parental occupation of unskilled/service workers, positive family history of cleft lip and/or palate, positive past history of artificial abortion, maternal smoking habits at first trimester, and maternal episodes at first trimester of suffering from any diseases and of ingesting any drugs, (b) A significantly decreased risk was linked with frequent maternal intake at first trimester of such animal proteins as meats, fishes and shells, eggs and milk, (c) Maternal drinking habits and radiation exposures, and frequent maternal ingestion of Japanese/black tea were not associated. (d) Maternal coffee drinking at first trimester significantly elevated the risk, but turned to be unrelated when maternal smoking habits were statistically corrected. (3) A cohort study of approximately 10,000 pregnants, which is ongoing from April 1989 in Nagoya and aims to disclose the associations of parental life‐style habits with general pregnancy outcomes including major congenital malformations, was briefly discussed.

Bendectin and human congenital malformations.

The relationship between Bendectin exposure during the first trimester of pregnancy and the occurrence of congenital malformations was prospectively studied in 31,564 newborns registered in the Northern California Kaiser Permanente Birth Defects Study. The odds ratio for any major malformation and Bendectin use was 1.0 (95% confidence interval 0.8-1.4). There were 58 categories of congenital malformations; three of them were statistically associated with Bendectin exposure (microcephaly--odds ratio = 5.3, 95% confidence interval = 1.8-15.6; congenital cataract--odds ratio = 5.3, 95% confidence interval = 1.2-24.3; lung malformations (ICD-8 codes 484.4-484.8)--odds ratio = 4.6, 95% confidence interval = 1.9-10.9). This is exactly the number of associations that would be expected by chance. An independent study (the Collaborative Perinatal Project) was used to determine whether vomiting during pregnancy in the absence of Bendectin use was associated with these three malformations. Two of the three (microcephaly and cataract) had strong positive associations with vomiting in the absence of Bendectin use. We conclude that there is no increase in the overall rate of major malformations after exposure to Bendectin and that the three associations found between Bendectin and individual malformations are unlikely to be causal.

Shaking rat Kawasaki (SRK): a new neurological mutant rat in the Wistar strain.

Shaking rat Kawasaki (SRK), a newly discovered neurological mutant rat in the Wistar strain, is described. The abnormalities of SRK rats are transmitted as an autosomal recessive trait. The neurological signs are shaking of the body and an ataxic-paretic gait from day 10 postnatal. The affected rats survive for about 1 month. Macroscopically, the cerebellum is small and frequently the vermis and paraflocculus lacking. The most conspicuous histological finding in the central nervous system is malposition of the neurons in the cerebral cortex, hippocampus and cerebellum. Myelination and synapse formation are intact. Abnormal myelinated fibers are present in the molecular layer of the cerebral cortex and in the central gray matter of the spinal cord. These morphological abnormalities resemble those reported in the reeler mutant mouse. SRK rats are another good animal model of human congenital malformations with neuronal migration disorders.

Frequency of Human Congenital Malformations

Birth defects are important health problems. They are the leading cause of infant mortality, the fifth leading cause of premature years of life lost, and important contributors to our nation's chronic disease burden. Researchers have been successful in finding a few causes of birth defects; however, the etiology of the majority of birth defects remains unknown and thus hampers our ability to prevent these diseases. Clinicians who care for patients with birth defects can play an important role in etiologic research by developing good and testable etiologic hypotheses. Epidemiologists must then use these hypotheses and those provided by scientists working with experimental animals to design studies that can test these hypotheses.

Teratogenic Effects of Maternal Coffee Consumption on Retinal Layers of Neonatal Mouse Eyes

Concern has been raised about the possible harmful effects upon the fetus of caffeine and freshly brewed coffee consumed during pregnancy. Caffeine has been linked to spontaneous abortion, small-for-dates babies, and congenital malformations in humans and to fetal resorption and fetal death in rodents. Animal studies with caffeine have demonstrated definite teratogenic effects upon fetuses exposed in utero. Caffeine and freshly brewed coffee have been used in animal experiments in which varied methods were employed to dose animals at specific gestational ages, but results from these studies proved inconclusive, particularly in regard to development of the eye. The current study, therefore, was undertaken to determine the effects, if any, of the maternal consumption of freshly brewed coffee upon the development of the retinal layers of the fetal eye.

Mechanisms of teratogenesis.

This review discusses the mechanisms involved in congenital malformations that are primarily environmentally produced. The etiology of human malformations in the 1st year of life is genetic in 20-25% of cases environmental in 9-10% of cases and unknown (polygenic or multifactorial) in the remaining instances. Environmentally produced malformations demonstrate stage sensitivity a dose-response relationship threshold effects and genetic variability. It has been suggested that mechanisms of teratogenesis include mutation chromosomal aberrations mitotic interference altered nucleic acid synthesis and function lack of precursors and substrates for biosynthesis altered energy sources enzyme inhibition osmolar imbalance altered membrane characteristics and other mechanisms. However the fact that an environmental agent can induce 1 of these pathologic processes does not guarantee that exposure will result in teratogenesis nor does it enable prediction of teratogensis in a human if an agent exhibits 1 of these characteristics in an experimental test system. Agents that have been proven to cause congenital malformations in humans include alcohol aminopterin and methotrexate androgens coumarin derivatives diethylstilbestrol diphenylhydantoin methylmercury oxazolidine-24-diones polychlorinated biphenyls progestins radiation tetracycline thalidomide and drugs used to treat maternal hyperthyroidism. Continued investigation of the etiology and mechanisms of teratogenesis is needed to prevent exposure to environmental teratogens.

Congenital malformations (second of two parts).

As the 1st part of this discussion of congenital malformations indicated there has been only limited success in identifying environmental chemicals that may be responsible for human congenital malformations. Attention in this discussion is directed to major environmental causes (occupational hazards chemicals of predilection or habituation pharmaceutical drugs anticonvulsant drugs cytotoxic drugs vaginal spermicides and nutrition); and prevention of congenital malformations. Of all substances and situations persons are exposed to at work only anesthetics have aroused more than a mere suspicion of prenatal harmfulness. An analysis of a large number of reports alleging that increased rates of congenital malformation and spontaneous abortion were induced by exposure of pregnant women to anesthetic gases concluded only that some evidence indicated an increased rate of spontaneous abortion. Recent findings emphasize that spontaneous abortion is a soft sign. Personal habits and preferences involving a variety of substances have been suspected of causing prenatal maldevelopment. They are coffee tea and alcohol drinking; cigarette smoking; tobacco chewing; toluene and gasoline sniffing; and drug addiction. Addictive drugs and agents have not been convincingly associated with congenital malformations although increased stillbirth rates reduced birth weight and neonatal withdrawal symptoms have consistently been found in studies of the most commonly used drugs--heroin and methadone. Recent studies would seem to have laid to rest the accusation of teratogenesis that had been charged against coffee and by inference other products containing caffeine. Only reduced birth weight has been found to be associated with heavy coffee drinking. Like coffee drinking and cigarette smoking the drinking of alcoholic beverages during pregnancy has been reported to have a great variety of effects on the unborn--abortion growth retardation defects of the central nervous system mental retardation and congenital structural anomalies. None of the drugs most frequently prescribed or self administered has been clearly or consistenly implicated as being teratogenic including aspirin which has come under suspicion. Many such medications have been either called into question or accused outright. Those for which such charges are considered by current medical opinion to be dubious or unproved are listed in a table. 2 studies indicate a possible role of a deficiency of folate in the development of neural tube defects but acceptance of this association should be reserved until expanded trials are completed. The causes of the majority of congenital defects are still unknown. In time some of these defects and some of those now included in the multifactorial group may be controllable. It is to the understanding and control of such conditions that efforts and resources should be turned.

Phylogeny and Its Clinical Significance

The creation of the universe, the origin of life, and the rise of the one celled organism to man are reviewed. The embryologic development of man recapitulates the entire phylogenesis. The evolution of the sense organs (ear and nose) and food and airway passages is discussed in detail. Finally, observations are made regarding phylogenetic development and its relation to human congenital malformations and other pathologic processes.

Certainty levels in the nullity method of symbolic logic application to the pathogenesis of congenital heart malformations

Investigating the pathogenesis of complex human congenital heart malformations involves special difficulties not usually encountered in studying human disease. Most malformations develop before clinical investigation is feasible, and reliable animal models are few. Virtually all advances in this field have come from thoughtful correlations of embryologic and patient observations. Symbolic logic is a natural medium for incorporating information of this nature into a mathematical and computer analysis, and has been recently employed in a study of the pathogenesis of the tetralogy of Fallot. The chief drawback of the symbolic logic approach, however, is its inability to handle uncertainty. This paper introduces an extension of the nullity method of symbolic logic which sorts patient observations and pathogenetic hypotheses into levels of certainty ranging from real data to reasonable preferences. A computer algorithm is presented which evaluates these levels of certainty, and the completeness and closure of this algorithm are proved mathematically. This computer algorithm identifies problem cases which are poorly explained by a given pathogenetic theory, and thus provides the initial step for refining the theory.

Sequential Atlas of Human Congenital Malformations. Observations of Embryos, Fetuses, and Newborns.

Sequential Atlas of Human Congenital Malformations. Observations of Embryos, Fetuses, and Newborns.

ALLELIC RESTRICTION: A BIOLOGIC ALTERNATIVE TO MULTIFACTORIAL THRESHOLD INHERITANCE

Contrary to the argument regarding the conservatism of the multifactorial threshold model for describing the inheritance of congenital malformations, little biological insight has resulted from the series of tautological, albeit grandiose, mathematical assumptions currently comprising the basis for this hypothesis. The working hypothesis of this presentation is to apply the "allelic restriction" model to the genesis of common human congenital malformations. New population data concerning isolated cleft palate closely fit the predictions of the proposed hypothesis. Recognising the heterogeneity of cleft palate as well as other common congenital malformations (namely, the difference between phenocopies, definable syndromes, and true hereditary cases), the "allelic restriction" model accords with the apparent greatly "reduced penetrance" of the hereditary cases. This model is meant to apply only to those congenital malformations which have both a high population frequency and a relatively small number of families showing an atypical type of vertical transmission.

The community of human malformation syndromes that shares ectodermal dysplasia and deformities of the hands and feet

Syndromes of human congenital malformation may be classified be recognizing communities of syndromes that share multiple phenotypic similarities involving their principal diagnostic features. A community of syndromes that shares various expressions of ectodermal dysplasia and various deformities of the hands and feet is proposed; these syndromes are divisible into two classes according to the presence or absence of anomalies in the nasal or labial regions of the face. The dysmorphogenetic validity of the division is supported by the fact that the syndromes without nasal or labial anomalies have a high frequency of sensorineural deafness as one expression of ectodermal dysplasia whereas those without such anomalies do not. The usefulness of such a syndromal community as a base for evolving a taxonomic scheme of dysmorphogenetic relatedness amongst different syndromes is illustrated.

A community of human malformation syndromes involving the Müllerian ducts, distal extremities, urinary tract, and ears.

Abstract“Syndrome fever” is a term used to characterize the prolific publication of “new” human congenital malformation syndromes in the last decade. One way to manage syndrome fever, that is, to assimilate and utilize efficiently its valuable informational by‐product, is to create nosologic communities composed of member‐syndromes which have close general and specific phenotypic similarities. The phenotypic community approach to human mal‐formation syndrome taxonomy is applicable to rare, family‐specific syndromes, to well‐known syndromes that have achieved firm, independent identities, and to mixtures of the two. A community of six syndromes, four of them apparently rare, is proposed. All share uterovaginal malformation, but neither this type nor any other single type of malformation is essential for a syndrome to merit membership in the community. Five of the six syndromes have distinc‐tive and and/or foot malformations. Four of the six share malformations of the urinary tract; in a fifth urinary incontinence probably reflects a subtle dysmorphism. Three of the six syndromes have anomalies of the aural appa‐ratus; in two this involves an association between severe renal dysgenesis and middle ear ossicle defects. The sharing of similar malformations involving several systems suggests that the respective causes of the syndromes act on the same developmental pathway(S). All six syndromes have occurred in a familial distribution; four are probably determined by major mendelian genes. Malformations of the axial skeleton are rare, but those of the distal extremities are common, in the familial syndromes belonging to the group. The reciprocal tendency is found in sporadic occurrences of severe uterovaginal dysgenesis (Rokitansky‐Küster‐Hauser syndrome) and in those with so‐called nonspecific female pseudohermaphroditism.

Etiology of congenital defects.

More than 30 years ago Gregg1 identified rubella virus as a cause of certain congenital defects. The discovery was important per se, since in times of rubella epidemicity the number of affected infants can be substantial. But the finding had a broader implication, for, heavy as the burden of rubella-induced defects may be, it represents only a tiny fraction of the total problem of human congenital malformation. Gregg's discovery offered hope that a major breakthrough was imminent in the identification of prenatal exposures responsible for the more prevalent malformations. That hope has not been fulfilled. A few factors — representative . . .

Congenital malformations and the problem of their control.

The possibility of preventing or reducing the prevalence of human congenital malformations is discussed in the light of current knowledge about their aetiology. The original data presented are derived from an epidemiological study of all the infants (92,982) born in the three years 1964-6 to women resident in a defined area of South Wales and all the congenital malformations (3,242) discovered in those infants by the second anniversary of their birth.

Single hit aetiology of human minor congenital malformations unassociated with major congenital malformations.

MINOR birth defects can be defined as anatomical variants which occur at low frequency in the normal population and, as distinguished from major malformations, have no clinical or cosmetic effects per se. Many syndromes associated with major defects such as the trisomies and rubella embryopathy also have a high incidence of minor malformations. Conversely, almost all minor defects which have been studied clinically are known to be more frequent in individuals with major malformations. The latter types of malformations have been shown to cluster in the sense that an individual with a major defect in one organ or system is more likely than an individual chosen at random to have a significant defect elsewhere1. But we have found that minor malformations in individuals without major malformations do not show such a tendency to cluster but rather are independent. Furthermore, our subsequent analysis of published data of other workers which bear on this problem supports this conclusion.

The susceptibility of the offspring of alloxan-diabetic mice to a teratogen

ABSTRACT Maternal diabetes, or pre-diabetes, has been considered as a possible factor in the aetiology of human congenital malformations by several investigators (De Costa, 1955; Hoet et al., 1960; Hiekkala & Koskenoja, 1961; Nicholson & De Maria, 1963; Pederson et al., 1964; Lenz & Maier, 1964). However, a few authors have reported no increase in the incidence of anomalies among infants of diabetic women (Given et al., 1950; Hall & Tillman, 1951; Rubin & Murphy, 1958). Alloxan-induced maternal diabetes in animals has also been studied, and an increase of stillbirth and foetal macrosomia has usually been recognized (Davis et al., 1947; Lindan & Morgans, 1950; Bartelheimer & Kloos, 1952; Angervall, 1959; Solomon, 1959; Kim et al., 1960; Loveeia/., 1960; Koskenoja 1961). The incidence of malformations, however, was not increased in most cases, the exception being those reported by Ross & Spector (1952), Fujimoto et al. (1958) and Watanabe & Ingalls (1963).

TERA TOLOGY

Tracing experimental mammalian teratology from its origin in the 1930's, Josef Warkany, MD, contrasted "the great possibilities of the future" in this field with "the limited achievements of the past." Warkany, a fellow of the Children's Hospital Research Foundation in Cincinnati, said that, although avian and amphibian eggs were used for experimentation during the last century, investigators concerned with human congenital malformations doubted that results from lower classes could be applied to mammals. They believed, rather, that the maternal organism protected the embryos and fetuses so well that teratogenic agents could not affect them, and that adverse environmental conditions, if they did not kill the embryos outright, left them completely untouched. The few observations which suggested that such factors as trauma, hemorrhage, amniotic anomalies, or large doses of x-ray could deform a fetus in utero were thought to be "rare and exceptional and completely insufficient to explain the bulk of

Clinical investigations on the etiology of human congenital malformations: Krone: p. 567

Clinical investigations on the etiology of human congenital malformations: Krone: p. 567