Virginia J. Baldwin

Biochemical abnormalities in rhizomelic chondrodysplasia punctata

Biochemical studies with emphasis on peroxisomal functions were conducted in six patients with well-documented rhizomelic chondrodysplasia punctata (RCDP) and compared with findings in patients with Zellweger syndrome and neonatal adrenoleukodystrophy (ALD). Patients with RCDP had three characteristic biochemical abnormalities: (1) profound defect in plasmalogen (ether lipid) synthesis, which is significantly greater than the analogous defect in Zellweger syndrome or neonatal ALD; (2) reduction of phytanic acid oxidation activity to 1% to 5% of control, similar to that observed in Refsum disease, Zellweger syndrome, and neonatal ALD; (3) presence of the unprocessed form of peroxisomal 3-oxoacyl-coenzyme A thiolase in the postmortem liver of two patients. Other peroxisomal functions were normal, including levels of very long chain fatty acids, pipecolic acid, and bile acid intermediates, and immunoblot studies of peroxisomal acyl-CoA oxidase and bifunctional enzyme in postmortem liver. Unlike what is observed in Zellweger syndrome and neonatal ALD, catalase activity in cultured skin fibroblasts was sedimentable, indicating that peroxisome structure is not grossly deficient in RCDP. The biochemical abnormalities in RCDP were consistent and set it apart from all the other known peroxisomal disorders.

Umbilical cord ulceration and intestinal atresia: a new association?

In three fetuses, congenital intestinal atresia was associated with linear ulcerations of the umbilical cord. In two cases, hemorrhage was seen from the cord ulcer. Both fetuses required emergency cesarean section for fetal distress and were born anemic. The third fetus was mildly hydropic, attributed to hemorrhage, and was stillborn. The mechanism of the association could not be determined. These cases suggest a risk of prenatal umbilical cord hemorrhage in infants with intestinal atresia.

Management of quintuplet pregnancy by selective embryocide

Selective embryocide was performed as a two-stage procedure in a patient with a quintuplet pregnancy in the first trimester. No complications occurred, and the patient was delivered of healthy twins at term. This procedure may be offered to selected patients with pregnancies with greater than five embryos.

Anomalous Development of Twins

As we learn more about the human genome and develop more sophisticated ways of studying diseases, disorders, and disturbed development, the borders between these abnormalities become harder to define. For example, as we learn more about the underlying biochemical defects in dwarfing syndromes such as thanatophoric dysplasia, this “malformation” becomes more like an inborn error of metabolism—a genetic defect or alteration with a specifically altered or absent product, leading to a predictable set of consequences depending on the role of that product. Considering this concept, it is perhaps somewhat artificial to discuss developmental/morphologic/structural anomalies separate from the sorts of diseases and disorders reviewed in Chapter 6. However, we are still a long way from defining the underlying molecular mechanisms in most structural variations from “normal,” so there is probably more we can learn from reviewing them in a broader context. Careful analysis of patterns of malformations and associated epidemiologic characteristics may help define where the basic defect could be looked for, and examinations of malformations in twins may provide particularly useful data.

Pathology of Intragestational Intervention in Twin-to-twin Transfusion Syndrome

Selective intervention in multiple pregnancy is being used to enhance the chances of survival of at least one conceptus when the risks for the combined conceptuses and mother are considered too great. These procedures have been applied to induced polyembryonic conceptions (selective continuance) and discordant dichorionic twins (selective birth). We report attempts at selective intervention in three monochorionic twin gestations affected by twin-to-twin transfusion syndrome. In all three cases, both fetuses seemed doomed and the mother was in significant distress. The selected survivor in the first case is doing well; both twins were stillborn in the second case; in the third case, the selected survivor died as a neonate but the other twin survived and is doing well. We suggest possible explanations for the clinical outcome of each case based on detailed pathologic examination of the delivered placentas and autopsy examination of the nonsurviving twins. The shared chorionic circulation is the source of both the clinical disorder and the potential complications of any attempt to alleviate the disorder. This situation is unique to monochorionic twins, and we discuss the implications of this for intrauterine therapy of twin-to-twin transfusion syndrome.

The Pathology of Monochorionic Monozygosity

One of the major concepts espoused in this volume is that placental form can be as important to the outcome of a twin conception as the genetic derivation of the conceptuses. The most clear-cut evidence for this concept is in monochorionic monozygotic twinning. Except for genetic considerations, monozygotic twins with dichorionic placentas have similar developmental and gestational risks as dizygotic twins. Monochorionic monozygotic twins, however, have two additional potential sources of problems—vascular anastomoses between the fetuses and/or abnormalities of duplication.1, 2 The consequences of aberrations of monochorionic twinning may be a pair of remarkably different so-called identical twins—an argument for avoiding the term as it is not only inaccurate but potentially confusing when counseling affected families. Some of the most bizarre anomalies of human reproduction are seen in these cases—as Antonio asks of Sebastian “How have you made division of yourself?” (Shakespeare, Twelfth Night, V, i).

The Placenta in Multiple Pregnancy

The pathologist’s contribution to the analysis of multiple pregnancy is twofold—surgical pathology of the placentation, and autopsy pathology of any deceased fetus(es) or infant(s). The easiest and most obvious examination is documentation of placental morphology, but unfortunately this is still often quite incomplete

Intertwin Vascular Anastomoses

One of the less well characterized aspects of the pathophysiology of twin pregnancies is the clinical and pathological significance of intertwin vascular anastomoses. These can be associated with marked intertwin growth discordancy, and may contribute to severe fetal compromise or death, or perinatal disability or death. These possible consequences are not only clinically important but also have been the subject of concern in disputes over poor perinatal outcome of twins. Thus, it is worthwhile to devote an entire chapter to a discussion of these anastomoses and their importance. In the first part of the discussion, intertwin anastomoses are defined as to their genesis, location and appearance, and anatomic and functional assessment. In the second part, potential patterns of pathologic hemodynamics are described, with their natural history and complications, diagnosis, and possible treatments. The pathologist has an extremely important contribution to make to the assessment of intertwin vascular anastomoses, in close collaboration with clinical colleagues caring for the mother and fetuses/infants, as will be noted throughout the discussion.

Morbidity of Twins

Infants of multiple gestations are subject to all the diseases and disorders that singletons are, but with two additional levels of consideration—the degree of concordance of the abnormality, and the significance of the twinship to the pathophysiology or prevalence. The caveats surrounding twin studies and the interpretation of the significance of concordance of an observation in twins have been discussed in Chapter 1. However, it is worth restating the importance of careful pathologic documentation of placental findings and autopsy studies to the validity of any study of patterns of disease in twins.

The Placenta—What The Pathologist Can Tell The Accoucheur

Abstract The pathologist with an interest in the placenta can often be of great help to the delivering clinician. Placental findings may explain clinical events during the pregnancy, clarify unusual results from prenatal investigations, and determine the cause of or contributing factors to perinatal morbidity or mortality. In all cases, it is recommended that the delivering clinician make a record on the mothers chart of the salient gross features of the placenta at the time of delivery. Not all placentas need to be sent for examination, especially if there is a system for holding the placenta available for a week after delivery. The best possible results from placental examination by the pathologist are when there is good communication with the clinician.