Polytopic anomalies with agenesis of the lower vertebral column.

We describe clinical, pathological and radiological findings in 15 cases of sporadic and familial lower spine agenesis with additional anomalies of the axial skeleton and internal organs and speculate about the cause and pathogenesis of this malformation complex. We show that all of these findings are defects of blastogenesis, originate in the primary developmental field and/or the progenitor fields, thus representing polytopic field defects. This concept appears applicable in our cases and makes such terms such as "caudal regression syndrome" or "axial mesodermal dysplasia spectrum" redundant.

German syndrome in sibs.

We present a male-female sib pair born to Ashkenazi Jewish parents with "arthrogryposis," hypotonia-hypokinesia sequence and lymphedema. Of all the "arthrogryposis" hypotonia syndromes, the condition in these sibs appears to be most like that of the patients of German et al [1975] and the patient of Salmon [1978]. They appear to be the first sib pair with German syndrome, which suggests autosomal recessive inheritance. Three of the four known families with affected children have been Ashkenazi Jews.

Rett syndrome--a review and discussion of syndrome delineation and syndrome definition.

The current status of clinical genetic and pathogenetic knowledge in Rett syndrome is reviewed and updated. Some of the concepts which are highlighted include among others, casual homogeneity vs heterogeneity; the difficulty of dealing with potential variability while the possibility of heterogeneity still exists; progress in examining genetic hypotheses. We review our experience with 8 new patients, note the evidence for the presence of congenital hypotonia in all and several instances of minor anomalies and again raise the issue of whether girls with the Rett syndrome are in fact normal from the time of birth and in early infancy until the characteristic phenotype is recognizable. Previous recommendations for standardized international history, examination and investigation protocols are strongly reinforced, and the question as to who should study brains of Rett syndrome patients is raised by a parent. As is the case in most conditions now being studied by molecular geneticists, finding a marker will be a major etiologic breakthrough, but the work of delineating the pathogenesis will remain to be done.

The developmental field concept in pediatric pathology--especially with respect to fibular a/hypoplasia and the DiGeorge anomaly.

Identical anomalies produced by different causes such as aneuploidy, gene mutation, teratogenic chemicals, and certain surgical procedures are a clear indication that embryonic primordia respond as units in the production of developmental anomalies of anatomic structure. Hence, they must also act as units during normal ontogeny. The presence of identical malformations in different mammalian species identifies developmental and anatomic homology by virtue of descent from a common ancestor. These dys- and orthomorphogenetically reactive units are the equivalents of the classic experimental embryologist's epimorphic fields, which are those units of the embryo in which the development of complex structures appropriate to the species is determined and controlled in a spatially coordinated, temporarily synchronous, and epimorphically hierarchical manner that expresses both species-nonspecific (that is, phylogenetic) and species-specific genetically coded developmental information. Thus, it is as important for pathologists as it is for clinical geneticists to steep themselves in the art and science of phenotype analysis and to be able to do all of those studies, including anthropometry, dermatoglyphics, and growth analysis, that are required to arrive at inferences of cause and pathogenesis from the phenotype. There is probably one other incentive besides the ethical and intellectual ones to do this and to do it as well as possible, namely, the medico-legal consequences. If pathologists fail to illuminate the causal genesis of a given case to aid in preventing recurrence, then, in short order, they might be held equally as liable as clinicians for missing high recurrence risk genetic diagnoses. These depressing considerations aside, it is important to close on a positive note. As at the outset, we want to emphasize once more that, without question, this is the most exciting time to be working in the field of developmental pathology. In this specialty a marriage is occurring of several types of investigational methods, ranging from humble morphologic studies to metabolic analysis to the most sophisticated designs of molecular biology, to produce new interdisciplinary approaches to the solution of the oldest intellectual problem confronting medicine--how does the "fabric of the human body" (in the immortal words of Vesalius) come about?(ABSTRACT TRUNCATED AT 250 WORDS)

The Montana Fetal Genetic Pathology Program and a review of prenatal death in humans.

Western medicine is being sensitized to the enormous extent of prenatal death in humans at a time when such deaths, occurring after the first missed period, involve to an ever increasing degree wanted pregnancies conceived by women with rising mean maternal age, decreasing mean fertility, and ever greater desire and intention to assure a good pregnancy outcome. Available data suggest that about two-thirds of human ova, embryos, and fetuses fail to reach birth or the end of the first year of life, with infant mortality of 1.06%, stillbirth rate of 8/1,000, abortion rate of about 15%, and death rate around the time of implantation estimated at 34%. Based on limited data on sperm, ova aspirated from Graafian follicles in infertile women, direct observation of a few implanting ova, the low rate of human fecundity, and the high failure rate of in vitro fertilization, it seems reasonable to suppose that about 30% of human ova perish at the time of fertilization and before implantation. Most of this prenatal death is attributable to chromosome abnormalities (aneuploidy and polyploidy), estimated to be present at the beginning of development in about half of all human ova or embryos. Parent's anguish about prenatal death and their desire to understand its causes and to prevent recurrence is putting the medical profession under severe pressure to provide diagnostic and counseling services and make available prenatal diagnosis and preventive approaches; this comes at a low point in the ability of Western medicine to respond adequately, especially in the fields of embryology and developmental genetics, clinical teratology, anatomical pathology, and genetic pathology. Unless drastic ameliorative measures are taken, the situation is likely to get much worse, since health insurance pays for only a minute fraction of costs involved and the number of pediatric pathologists devoting major effort to this work in North America has dwindled to a small number without great hope for replacement from younger ranks, primarily as a result of the lack of incentive by the tertiary centers to make fetal genetic pathology ("morphology") an attractive field to work in. Here we report an effort by a secondary care center to provide such a service--presently more on demand than as systematic effort to reach all at need--in a huge, underpopulated state with birthrate of less than 13,000 and lacking any specially trained pathologist with a strong interest in the field.(ABSTRACT TRUNCATED AT 400 WORDS)

Fibular a/hypoplasia: review and documentation of the fibular developmental field.

Fibular aplasia and/or hypoplasia is documented as a developmental field defect and the extent of the fibular developmental field is delineated. The term fibular a/hypoplasia denotes the clinical spectrum of fibular deficiency in different patients and also implies that aplasia can be present in one limb and hypoplasia in the other. Causal heterogeneity of fibular a/hypoplasia is demonstrated, thereby defining it as a developmental field defect. Most cases of fibular a/hypoplasia are isolated, sporadic events. An autosomal dominant form of isolated fibular a/hypoplasia with ankle joint anomaly is reviewed. Fibular a/hypoplasia may be part of more complex sporadic dysostoses; sporadic syndromes, an aneuploidy syndrome; several autosomal dominant and autosomal recessive conditions. Fibular a/hypoplasia is also postulated to occur as a result of disruption or teratogenic insult; in animals, fibular development can be disturbed by radiation, busulfan, and retinoic acid. Clinical data allow evaluation of the extent of the fibular developmental field of the lower limb. This appears to include the pubic portion of the pelvis, proximal femur (distal half being apparent tibial developmental territory), patella, anterior cruciate ligament, and lateral and/or axial foot rays (but "never" the hallux and almost never associated with polydactyly). The rare cases of fibuloulnar dimelia allow confirmation of the well known homology of mesomelic limb segments responsible for concordant ulnar and fibular (and radial and tibial) defect, if both upper and lower limbs are involved in a given condition. Because fibular a/hypoplasia is the commonest of the mesomelic paraxial hemimelias, is usually nonsyndromal, and in most cases is apparently nongenetic (ie, with negligible recurrence risk), we propose that in humans, as in several other tetrapods, the fibula is undergoing regressive evolution and hence is developmentally especially labile.