Pediatric and Developmental Pathology 6, 361–364, 2003 © 2003 Society for Pediatric Pathology

Book Reviews Conjoined Twins: Developmental Malformations and Clinical Implications Rowena Spencer. The Johns Hopkins Press, Baltimore, MD, 2003. 476 pages, $85.00 (hardback). DOI: 10.1007/s10024-003-4038-x This book represents many years of dedicated study by a respected pediatric surgeon with a passionate interest in conjoined twinning. Her extensive clinical experience and unparalleled familiarity with 20th century case reports led me to expect a superb treatise on clinical and anatomical aspects of this subject. It was disappointing to find the book to be centered primarily upon her controversial theory of embryogenesis. Embryological speculation occupies many pages that could have been devoted to topics relevant to the expertise of the author and the needs of her clinical colleagues. Many challenging technical and ethical problems involved in the management of conjoined patients are ignored, and most of the others are given only brief attention. Illustrations, an indispensable feature of any treatise on conjoined twinning, are relatively sparse and unhelpful, with virtually no illustrations of internal anatomy. Most of the figures are diagrams based upon her embryological speculations, or drawings and photos of external features. The surgeon, pathologist, or radiologist puzzling over the anatomical peculiarities of a case of conjoined twins will likely be disappointed by the relative paucity of detailed anatomical description and useful illustrations in this book. A positive feature is the bibliography, which cites a substantial portion of the 20th century literature in English on conjoined twinning in humans, along with occasional references in German and French (including numerous misprints), and a few from previous centuries. This list includes many references from years not covered by Medline searches. Also welcome are tables listing certain features of cases in some of her categories of twinning. The embryological theory of the author is that all conjoined twins result from fusion of separate germ discs. This is presented with an evangelistic zeal that betrays a lack of objectivity, with few qualifications or expressions of doubt. She assumes that all patterns and degrees of twinning are due to the same mechanism, and that fusion and fission are the only two mechanisms requiring consideration, so that disproof of one proves the other.

Concepts that might apply to some cases are applied universally. For example, on page 416, the author expresses without qualification the opinion that teratomas are parasitic conjoined twins. Her discussion of the theoretical embryology of “parapagus” twinning (pages 246 –247) provides a particularly disturbing example of fundamental convictions based upon unconvincing evidence. She dismisses fission as the mechanism of rostral duplications in the following words: 1. Bifurcation of a single notochord has been proposed (Machin and Sperber, 1991), but as the notochord probably elongates by proliferation at the caudal aspect (O’Rahilly, 1998), bifurcation during growth should result in caudal, not cranial duplication [italics mine]. The implied support of a leading authority on embryology lends an aura of respectability to this statement. However, the only reference provided is to a personal communication, and the adverb “probably” seems to be given the status of certainty. That statement constitutes one of two chief arguments offered as proof that “parapagus” twinning results from fusion of originally separate germ discs. The other argument is presented in the following words (p. 246): 1. In a review of the entire spectrum of parapagus—it might seem logical to assume that they arise from two separate, nearly parallel notochords on one embryonic disc, very close together caudally but with varying degrees of separation rostrally. However, secondary fusion of two separate embryonic discs is indicated by the indisputable evidence of duplication of some portion of the umbilicus, umbilical cord, or placenta in a few parapagus [italics mine]. The reasons why these few “indisputable” cases so conclusively prove her point are not explained further. No details are provided concerning these cases, and I searched in vain for reference to where they were published. On page 254, it is mentioned that these cases comprised 2% (i.e., 6) of her 305 pairs of “parapagus” twins. On page 246, it is mentioned that three of them were characterized by “an additional umbilical vessel,” without noting whether these were arteries or veins, or how their number was documented. Accessory umbilical vessels can result from several developmental mecha-

nisms other than fusion of separate embryonic discs. These six “indisputable” cases, plus the aforementioned reference to a statement by Dr. O’Rahilly, are considered sufficient to justify the following sweeping generalization (p. 246): 1. All things considered, then, it is postulated that all conjoined twins, including the parapagus, arise from two individual notochords on two originally separate embryonic discs [italics mine]. Dr. Spencer’s speculations on the fusion-fission controversy resurrect a debate that was popular during the 18th and early 19th centuries, when embryology was primarily the domain of philosophers. During the latter part of the 19th century, this question was subjected to scientific investigation, especially in the great embryological laboratories of Germany. It was soon recognized that the original philosophical concepts, designated in German as the “Spaltungstheorie” and “Verwachsungstheorie” (“fission” and “fusion” theory), were too simplistic. Though the evidence was more favorable to the “fission” theory (i.e., incomplete separation of monozygotic twins), it was also apparent that the induction and organization of body axes was more complex than these terms implied. Fusion versus fission was rephrased in terms more relevant to evolving concepts of developmental mechanics. The monographs of Schwalbe [1] and Hu¨ bner [2] provide detailed overviews of experimental studies into the developmental mechanisms of conjoined twinning in the decades preceding the First World War. Hu¨ bner’s monograph [2], published in 1911, includes an appropriate epitaph for the simplistic fusion-fission controversy (p. 792): 1. ⬘Verschmelzung’ oder ⬘Spaltung’, dies beiden Worte, die einst so heftige Discussionen verursachten, sind heute blosse Worte [⬘Fusion’ or ⬘splitting,’ these words that once provoked such violent controversy, are now empty words]. In 1923, Newman’s analytical review of the embryology of twins [3] added several new arguments refuting fusion as the mechanism for most cases of conjoined twinning, and that concept received little support in the following decades. The experimental embryology of conjoined twinning has now been extended to the molecular level. One model involves the production of axial duplications in xenopus larvae by injection of components of the Wnt/beta-catenin cascade at the 2 to 8-celled stage [4,5]. Comparable results are reported in zebrafish [6]. The formation and development of two-headed embryos and other axial duplication anomalies can be observed continuously in vivo. These and numerous other experimental models developed over more than a century provide substantial evidence inconsistent with Spencer’s fusion theory of “parapagus” twinning. The existence of that literature is briefly mentioned in Spencer’s chapter

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2, but is dismissed on the basis that animal models do not necessarily apply to humans. Perhaps experimental embryology would not have been dismissed so casually if it had provided more support for her speculations. Armchair embryology may suffice for politicians and theologians, but is a poor substitute for descriptive and experimental science. Chapter 9 is devoted to the “rachipagus” pattern, a novel category of conjunction introduced by Dr. Spencer in 1995 [7]. She considers this to be the pattern providing the most convincing proof of her developmental theory. Twins joined back-to-back, with fusion of spinal columns above the sacrum, were not believed to exist until Dr. Spencer discovered a suggestive case report in a French regional medical journal [8]. That report (which I have not seen) was a radiographic study of 7-month fetuses said to be joined back-to-back. No photographs or anatomical details are provided. The radiograph, as reproduced on page 333 and in Spencer’s 1995 article, depicts two individuals that appear to have posterior fusion of skulls, two faces directed in opposite directions, and apparent coalescence of vertebrae T6 to L3. The spinal columns diverged in the lumbar and cervical regions. The reproduced image is small and somewhat fuzzy. Though it appears impressive, it conceivably could be misleading. “Janiform” cephalothoracopagus twins, connected ventrally from umbilicus to vertex with two composite faces oriented in opposite directions, might yield a similar appearance if the orientation of the radiograph was perpendicular to the midfacial axis, with the two spinal columns partially superimposed, and each pelvis was rotated approximately 90 degrees to face the same direction as one of the faces. A few bizarre cases reported in Table 9-1 and in a 1996 article by Spencer et al. [9] are offered as possible examples of rachipagus twinning, but none provides convincing proof of her interpretation. Taruffi’s monumental review of the world literature up to the early 1880’s [10] disclosed no anatomically confirmed case similar to that depicted in the French radiological paper, and a Medline search reveals no recent reports of similar cases. Furthermore, I have not found a convincing description of this type of twinning in another vertebrate species. Before adding the rachipagus pattern to the list of established patterns of conjoined twins, I would like to see more anatomical evidence than the aforementioned single radiograph. The designation of rachipagus is not my only concern about the classification scheme and nomenclature proposed by Dr. Spencer, which is based primarily upon her embryological theory. It adds new areas of confusion and controversy without resolving old ones. Simplification is achieved by lumping the most difficult and controversial patterns of twinning together into a single “atypical” category. Novel words are introduced and older terms are given new meanings. While insisting upon precision in the application of some terms, she is

imprecise in others. For example, “omphalopagus” has long been used for ventral supraumbilical conjunction confined to the umbilicus or cord, but Dr. Spencer extends the use of this term to all cases in the thoracopagus series with separate hearts, regardless of the degree of thoracic conjunction. Cardiac anatomy is so dominant a consideration in the surgical evaluation of conjoined twins that there is no obvious need to incorporate it into the name of the twinning pattern at the cost of anatomical precision. Creation of the “parapagus” category is, in my view, a particularly unfortunate one. This designation is proposed for a spectrum of patterns traditionally viewed as axial duplications, most often observed in the anterior (or rostral) end of the axis. The “parapagus” designation reflects Spencer’s fusion theory, which seems unlikely to achieve wide acceptance. Existing designations for rostral and caudal axial duplications accurately describe the anatomy of this pattern, and are consistent with the findings of experimental and descriptive embryology. Without belaboring all my reservations about this classification scheme, I will simply offer the opinion that problems involving conjoined twins are not likely to be resolved by new taxonomies. In the molecular era, new paradigms might lead to entirely different ways of thinking about twinning, but until then I plan to muddle along with the familiar imperfections of existing terminologies rather than accepting this new one. My affection and respect for the author, with whom I have enjoyed a cordial correspondence for many years, makes it especially painful to express so many negative comments about a book that represents so much time and effort, and is so dear to her heart. My disappointment in this book reflects the height of my expectations. If only she had left embryology to embryologists and focused upon clinical anatomy, she could have created a splendid work of permanent value. In spite of its disappointing features, it is the most extensive monograph on this topic in the English language, and contains information not easily found elsewhere. It therefore deserves a place on the shelves of those who deal with these amazing and eternally challenging patients. J. Bruce Beckwith Department of Pathology and Human Anatomy Loma Linda University Loma Linda, CA, USA e-mail: [email protected]

REFERENCES 1. Schwalbe E. Morphologie der Missbildungen des Menschen und der Tiere, Teil II: Die Doppelbildungen. Jena, Germany: Gustav Fischer, 1907. 2. Hu¨ bner H. Die Doppelbildungen des Menschen und der Tiere. Ergebnisse der Allgemeinen Pathologie und Pathologischen Anatomie des Menschen und der Tiere 1911;15: 649 –796.

3. Newman HH. The Physiology of Twinning. Chicago: University of Chicago Press, 1923. 4. Molenaar M, van de Wetering M, Oosterwegel M. XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell 1996;86:391–399. 5. McMahon AP, Moon RT. Ectopic expression of the protooncogene int-1 in xenopus embryos leads to duplication of the embryonic axis. Cell 1989;58:1075–1084. 6. Kelly GM, Erezyilmaz DF, Moon RT. Induction of a secondary embryonic axis in zebrafish following the overexpression of beta-catenin. Mech Dev 1995;53:261–273. 7. Spencer R. Rachipagus conjoined twins: they really do occur!. Teratology 1995;52:346 –356. ´ tude 8. Betoulieres P, Caderas de Kerlau J, Gevaudand L. E radiologique de squelette d’un monstre double janicephalerachipage. Montpellier Med J 1960;58:30 –39. 9. Spencer R, Chuaqui B, Garcia CJ. Anencephaly, dorsal hypermelia, and duplication of the vertebral column: a rare type of rachipagus conjoined twins. Teratology 1996;53: 253–260. 10. Taruffi C. Storia dell Teratologia, 8 volumes. Bologna, Italy: Regia Tipografica, 1881–1894. Published online June 6, 2003.

Clinical Use of Pediatric Diagnostic Tests Enid Gilbert-Barness and Lewis A. Barness. Lippincott Williams & Wilkins, Philadelphia, PA, 2003. 989 pages, $59.95 (paperback). DOI: 10.1007/s10024-003-5050-x Clinical Use of Pediatric Diagnostic Tests is an unique compendium of clinical criteria, laboratory tests, and other diagnostic studies for pediatric diseases. The format of lists, tables, and terse prose is similar to Wallach’s Interpretation of Diagnostic Tests, now in its 7th edition (Lippincott Williams & Wilkins, 2000). Indeed, many paragraphs of Clinical Use of Pediatric Diagnostic Tests have been borrowed whole or in part from Wallach. However, Drs. Enid Gilbert-Barness and Lewis A. Barness have taken this genre to the next level through the inclusion of concise clinical descriptions, and numerous lists and tables of their own creation or from a wide variety of sources. The 25 chapters deal with normal values; acid-base disorders; prenatal testing; neonatal disorders; infectious and immunologic diseases; laboratory tests specific to organ systems, including the eye and skin; and metabolic, genetic, nutritional, and toxic diseases. Each chapter contains a wealth of information, logically organized, and evidencing the remarkable breadth and depth of the expertise of the Drs. Barness. As one might expect from the team that gave us Metabolic Diseases: Foundations of Clinical Management, Genetics, and Pathology (Eaton Publishing, 2000), the lists, tables, and discussions in the chapter on metabolic and hereditary diseases are masterful, and may, alone, be worth the purchase price of this book. However, the introductory chapter not only provides reference ranges for most nonhematologic tests (which are tabulated in the chapters on hematologic and coagulation disorders),

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but also includes tables on preanalytical factors that can affect results (from a manual produced by the Royal College of Pathologists of Australasia), and pathologic and artefactual conditions that can elevate or lower the results of common blood chemistry tests (from a continuing education series published by the American Academy of Pediatrics); this eclectic collection of pertinent resources continues throughout the book. The inherent dangers in producing a book such as this are, first, that in a rapidly changing field like laboratory medicine, it is inevitable that some information will be outdated even prior to publication; and second, that listing all possible tests for a condition may give the nonspecialist, who is most likely to consult such a concise and comprehensive source, the impression that all are necessary. The authors admirably address the first concern in the chapter on metabolic and hereditary diseases by providing the reader with Internet addresses to several excellent websites. Similar references in other chapters to the websites of appropriate national organizations or reference laboratories would have been useful. During the preparation of this review, I referred to Clinical Use of Pediatric Diagnostic Tests when queried by clinicians about test selection. I generally found detailed information in the book, but in many cases would have given less than optimal advice if I had not searched further. For example, the discussion of celiac disease on page 286 indicates that antigliadin antibodies “provide a useful screening test,” that titers of antibodies to reticulum [sic] and endomysium are “the most specific noninvasive tests,” and that an enzyme-linked immunosorbent assay (ELISA) test for antitransglutaminase antibodies has been developed. For the past few years, however, pediatric gastroenterologists have utilized antiendomysial and antitissue transglutaminase antibodies as the principal screening tests, have largely limited assays for antigliadin antibodies to children ⬍ 3 years of age, and have dropped screening for antireticulin antibodies from their diagnostic regimen.

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The danger of inadvertently promoting over-ordering of laboratory tests is not at all unique to Clinical Use of Pediatric Diagnostic Tests; in fact, these authors go further than most in attempting to place the role of diagnostic studies in the appropriate clinical context. The introductory comments about thrombophilia on page 463 appropriately caution that testing after an acute thrombotic event should be limited to DNA-based tests, because functional assays of coagulation and anticoagulation factors may be spuriously elevated or lowered during this period. However, the listing of recommended tests for thrombophilia in children on page 468 and the flow chart for the interpretation of results on page 469 (which is where the reader is referred if he or she looks up “thrombophilia, laboratory tests in” in the index) lists a combination of DNA-based and functional assays without comment as to which should or should not be performed immediately after the acute event. In all likelihood, therefore, all of the tests would be ordered (at a cost of hundreds, if not thousands, of dollars), and half of the results would be uninterpretable. It is especially unfortunate that the relevant caveat in this case is only a few pages away, and might have been addressed by a note “to see page 463.” In their preface, the authors express the hope that Clinical Use of Pediatric Diagnostic Tests would meet the needs of a wide audience—pediatricians and family practitioners, pathologists, house officers, medical students, nurses, and laboratory technicians. This is a tall order, but this book fills an important niche as a first source for concise information on both the clinical and laboratory aspects of pediatric diseases. Theodore J. Pysher Department of Pathology Primary Children’s Medical Center University of Utah School of Medicine Salt Lake City, UT, USA Published online June 20, 2003.