Hirschsprung's disease and allied disorders with 49 tables

416 Pages·2007·0.34 MB·English

by  Alexander Matthias Holschneider

A. M. Holschneider · P. Puri (Eds.)
Hirschsprung´s Disease and Allied Disorders
A. M. Holschneider · P. Puri (Eds.)
Hirschsprung´s
Disease and Allied
Disorders
Third Edition
With 318 Figures and 49 Tables
123
A.M. Holschneider, MD
Immenzaun 6a
51429 Bergisch Gladbach
Germany
and
Former Head of The Children’s Hospital of Cologne
Amsterdamerstraße 59
50735 Cologne
Germany
P. Puri, MS, FRCS
Children’s Research Centre
Our Lady’s Hospital for Sick Children
Crumlin, Dublin 12
Republic of Ireland
Library of Congress Control Number: 2006934462
ISBN 978-3-540-33934-2 Third Edition Springer Berlin Heidelberg New York
First edition published by Hippokrates Verlag GmbH, Stuttgart / Thieme-Stratton Inc.,
New York 1982
Second edition published by license under the Harwood Academic Publishers imprint,
part of The Gordon and Breach Publishing Group, Amsterdam 2000
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Foreword
Drs. Holschneider and Puri have again given me the has been working in this particular area in the laboratory
honor of writing the foreword to this magnificent new for many years, and we all grateful for his efforts and his
edition of their book. contribution.
This book will continue to be recognized as the most The chapter on immunohistochemical studies written
comprehensive and well-documented text ever written by Dr. Rolle and and Dr. Puri summarizes the very excit-
on this subject. This new edition expands the horizons ing advances in this type of diagnosis.
of our knowledge of difficult and challenging conditions An additional chapter by Dr. Milla on adynamic bowel
such as Hirschsprung’s disease. syndrome expands our knowledge on the spectrum of
Dr. Grosfeld, a prestigious professor of pediatric sur- motility disorders of the bowel and urinary tract.
gery, was invited to write on the historical perspective of Finally, Dr. Somme and Dr. Langer have written an
Hirschsprung’s disease, and he has done so with a charac- additional chapter on the transanal pull-through proce-
teristically masterful style. dure for the treatment of Hirschsprung’s disease. There
The chapter on the pathophysiology of Hirschsprung’s is no question that this new therapeutic approach repre-
disease is now written by Dr. Puri and Dr. Montedonico. sents a very important contribution to the treatment of
Dr. Moore has written a very interesting chapter this condition.
on congenital anomalies and genetic associations in Again, we applaud the efforts of the editors in select-
Hirschsprung’s disease. The chapter on radiological diag- ing a group of talented experts and innovators to contrib-
nosis is now written by Dr. Kelleher. ute to what is still the best book on the subject.
This edition of the book characteristically continues to
expand upon the genetic basis of the condition. Dr. Puri Alberto Peña, MD
Preface
Hirschsprung’s disease is one of the most important and parison of the results of Swenson’s, Soave’s, Duhamel’s
most fascinating diseases in paediatric surgery. Our un- and Rehbein’s techniques was achieved.
derstanding of Hirschsprung’s disease is developing rap- However, as our understanding of Hirschsprung’s dis-
idly, not only in relation to its pathophysiology and the ease and associated motility disorders of the gut increased,
development of new surgical techniques, but especially a second edition of this book was published in 2000, this
in relation to new genetic findings. A first comprehen- time by Harwood Academic Publishers, part of the Gor-
sive description of the pathophysiology, clinical symp- don and Breach Publishing Group. The title of this new
toms, diagnosis and therapy of Hirschsprung’s disease book was changed to “Hirschsprung’s Disease and Allied
was outlined in 1970 by Theodor Ehrenpreis, Professor Disorders”, because we included other enteric plexus dis-
of Pediatric Surgery at the Karolinska Institute, Stock- orders and smooth muscle disorders of the gut. The edi-
holm, Sweden, in a booklet entitled “Hirschsprung’s Dis- tors of this again multiauthored edition were Alexander
ease”. The booklet of 176 pages was dedicated to Harald Holschneider and Prem Puri. The book was divided into
Hirschsprung (1830–1916) of Copenhagen, Denmark, three parts: Physiology and Pathophysiology, Clinical As-
and to Ovar Swenson of Chicago, Illinois, USA, the two pects, and Treatment and Results. As well as discussion of
pioneers in the study of Hirschsprung’s disease. Harald normal colonic motor function and the pathophysiology
Hirschsprung was a paediatrician, and Ovar Swenson of classical Hirschsprung’s disease, the book included spe-
a paediatric surgeon, who performed the first success- cial chapters on the development of the enteric nervous
ful resection of an aganglionic bowel segment. That first system, the functional anatomy of the enteric nervous
book, published by Yearbook Medical Publishers, mainly system, animal models of aganglionosis, the molecular
discussed questions of postoperative continence based on genetics of Hirschsprung’s disease and the RET protein in
the results of a large series of patients treated successfully human fetal development and in Hirschsprung’s disease.
at the Karolinska Institute. New areas of special interest included intestinal neuronal
In 1978 Ehrenpreis permitted one of the editors of the dysplasia, particular forms of intestinal neuronal malfor-
present edition to prepare an update of his internation- mations, enterocolitis, megacystis-microcolon-intestinal
ally recognized book. Therefore, in 1982, a new book on hypoperistalsis syndrome, degenerative hollow visceral
Hirschsprung’s disease by Alexander Holschneider was myopathy mimicking Hirschsprung’s disease, and newer
published by Hippokrates (Thieme-Stratton) with a fore- diagnostic techniques such as special neuronal markers,
word by Th. Ehrenpreis. It was a multiauthored textbook electron microscopy and anal sphincter achalasia. This
with particular prominence given to the results of an in- second edition was the most comprehensive book ever
ternational clinical research study of the postoperative published on Hirschsprung’s disease and allied disor-
results in Hirschsprung’s disease, undertaken from 1976 ders.
to 1978 by the author himself and a technical assistant, With the passage of time, our understanding of en-
with special regard to the underlying surgical techniques. teric plexus disorders has exploded. Ehrenpreis in his
The follow-up studies were performed with the help of preface of 1970 cited the President of the Swedish No-
the Volkswagen Foundation in 16 paediatric surgical de- bel Prize Committee who stated that there are more sci-
partments in Europe and the United States over a period entists living today than during all past centuries. After
of 3 years. The most interesting and unique aspect of this having reviewed the recent literature on Hirschsprung’s
study was the fact that all clinical and electromanometri- disease and allied disorders we are convinced that this
cal investigations were performed by the same research is even more relevant today. Therefore, a new edition
team, independent of the staff of the individual hospital. of Hirschsprung’s disease and allied disorders was real-
As a result of this study concept, a most objective com- ized with the help of Springer. The previous chapters
VIII Preface 
“Clinical Generalities of Hirschsprung’s Disease”, “Dis- third edition of the book both parts of each chapter deal-
orders and Congenital Malformations associated with ing with a specific surgical technique have been brought
Hirschsprung’s Disease”, “Megacystis-Microcolon-Intes- together to create new contributions for each of the dif-
tinal Hypoperistalsis Syndrome”, “Degenerative Hollow ferent surgical approaches. The chapter “Laparoscopically
Visceral Myopathy Mimicking Hirschsprung’s Disease” Assisted Anorectal Pull-through” has been updated and a
and “Diagnosis of Hirschsprung’s Disease and Allied Dis- new chapter “Transanal Pull-through for Hirschsprung’s
orders” have been updated. A new separate chapter on Disease” has been introduced. Finally, the previous chap-
“NAPDH-Diaphorase Histochemistry” has been intro- ters dealing with early and late complications have also
duced in the part “Diagnosis”, next to the updated chapters been brought together and the contribution of Teitel-
“Histopathological Diagnosis and Differential Diagnosis baum and Coran on long-term results and quality of life
of Hirschsprung’s Disease”, “Immunohistochemical Stud- has been updated.
ies” and “Electron Microscopic Studies of Hirschsprung’s The new edition is again a multiauthored book, and
Disease”. For reasons of clarity, previously separated we have to thank all the internationally well-known au-
chapters such as the former chapters 5 and 6 “Molecu- thors and coauthors for their excellent and sophisticated
lar Genetics of Hirschsprung’s Disease” and “Ret-Protein contributions. It is their interest, help and effort that has
in Human Foetal Development and in Hirschsprung’s again made possible the drawing together in one volume
Disease” have been brought together and concentrated of the collective wisdom of many of the leading experts in
in a new chapter. Chapter 3 “Functional Anatomy of the Hirschsprung’s disease and related disorders. Their con-
Enteric Nervous System” by M.D. Gershon and chapter tributions to this volume again provide a step forward in
6 “Normal Colonic Motor Function and Relevant Struc- the elucidation of the genetic basis, and the correct di-
ture” by J. Christensen have been reproduced. Chapter 12 agnosis and treatment of this interesting disease and its
“Particular Forms of Intestinal Neuronal Malformations” allied disorders.
and chapter 14 “Megacolon in Adults” have become part Besides the authors and coauthors, we would like to
of the new chapter 8 “Hirschsprung’s Disease: Clinical thank Mrs. Elisabeth Herschel of the Children’s Hospi-
Features” and chapter 18 “Neurocristopathies and Partic- tal of Cologne, and the Children’s Medical and Research
ular Associations with Hirschsprung’s Disease”. Chapter Foundation, Our Lady’s Children’s Hospital, Dublin, for
17 “Intestinal Obstructions Mimicking Hirschsprung’s their support. Finally, we wish to thank the editorial staff
Disease” has become chapter 21 “Adynamic Bowel Syn- of Springer, Heidelberg, Germany, particularly Ms. Ga-
drome”. briele Schroeder, for their interest and encouragement to
The chapters referring to the different surgical tech- publish a third edition of this book on a most important
niques have been updated too, but the concept of the subject in paediatric surgery.
previous editions, to compare the detailed description of
one of the pioneer surgeons with the experience of a sec- Alexander M. Holschneider
ond author with the same technique, was given up. In the Prem Puri
Contents
1  Hirschsprung’s Disease: A Historical  3.8 The Development of the ENS is Probably
Perspective — 1691–2005 .................... 1 Influenced by a Neurotrophin ......... 28
J. L. Grosfeld 3.9 NT-3 Promotes the Development
of Enteric Neurons ................... 29
3.10 The Development of the ENS is Probably
Influenced by a Cytokine .............. 31
2  Development of the Enteric Nervous System 13 3.11 An Aganglionosis Similar to That
P. Puri and U. Rolle in Hirschsprung’s Disease Occurs
in ls/ls and sl/sl Mice .................. 32
2.1 Introduction ......................... 13 3.12 Genetic Abnormalities in Genes
2.2 Embryonic Origin of ENS ............. 13 Encoding Endothelin-3 or its Receptor,
2.3 Origin and Development of Neural Endothelin-B, are Associated
Crest-Derived Cells ................... 14 with Spotted Coats and Aganglionosis .. 32
2.4 Functional Development of the ENS ... 15 3.13 An Action of EDN3 on Crest-Derived
2.5 Development of Intestinal Motility ..... 15 Precursors Does Not, by Itself, Account
2.6 Genes Involved in ENS Development .. 15 for the Pathogenesis of Aganglionosis .. 33
2.7 Other Factors Implicated in the Control 3.14 The Pathogenesis of Aganglionosis
of ENS Development ................. 17 Is Not Explained by an Abnormality
2.8 Conclusions .......................... 17 Limited to Crest-Derived Neural
Precursors ........................... 34
3.15 The Extracellular Matrix is Abnormal
3  Functional Anatomy   in the Presumptive Aganglionic Bowel
of the Enteric Nervous System ............... 21 of ls/ls Mice .......................... 35
M. D. Gershon 3.16 Laminin-1 Promotes the Development
of Neurons from Enteric Cells of Neural
3.1 Introduction ......................... 21 Crest Origin ......................... 36
3.2 The Normal Enteric Nervous System ... 22 3.17 The Effect of Laminin-1 on Enteric
3.3 Organization of Enteric Neurons ....... 23 Neuronal Development Depends
3.4 The ENS is Derived from the Neural on the Binding of its α1 Chain
Crest ................................ 23 to LBP110 ........................... 36
3.5 The Crest-Derived Cells that Colonize 3.18 The Effects of Laminin-1 on Crest-
the Gut are Originally Pluripotent Derived Cells Immunoselected from
and Migrate to the Bowel Along the Fetal Bowel Are Different from
Defined Pathways in the Embryo ...... 25 those of Laminin-1 on Cells Isolated
3.6 Enteric Neurons are Derived from More from the Crest Itself .................. 37
Than One Progenitor Lineage .......... 25 3.19 Premature Neuronal Differentiation May
3.7 Dependence of Enteric Neuronal Subsets Result When Inadequately Resistant
on Different Microenvironmental Progenitors Encounter an Excessively
Signals (Growth/Differentiation Factors) Permissive Extracellular Matrix ........ 38
Defines Sublineages of Precursor Cells: 3.20 Both Crest-Derived and Non-Neuronal
RET and Glial Cell Line-Derived Cells of the Colon Probably Respond
Neurotrophic Factor .................. 27 to EDN3 ............................. 38
 Contents
3.21 Interstitial Cells of Cajal are Present, 7.4 The Gut in Hirschsprung’s Disease .... 100
but Abnormal, in the Aganglionic Bowel 7.5 Gut motility in Hirschsprung’s Disease 102
of Hirschsprung’s Disease ............. 39 7.6 Final Remarks ....................... 103
3.22 Hirschsprung’s Disease is Associated
with Many Different Genetic
Abnormalities: Conclusion From 8  Hirschsprung’s Disease: Clinical Features ... 107
Animal Models ....................... 40 P. Puri and S. Montedonico
3.23 Summary ............................ 40
8.1 Introduction ........................ 107
8.2 Incidence ........................... 107
4  Animal Models of Aganglionosis ............ 51 8.3 Classification ........................ 107
A. M. Alzahem and D.T. Cass 8.4 Sex ................................. 107
8.5 Race ................................ 108
4.1 Introduction ......................... 51 8.6 Heredity ............................ 108
4.2 History .............................. 51 8.7 Clinical Presentation ................. 110
4.3 Histologic Anatomy .................. 52
4.4 Physiology ........................... 53
4.5 Embryologic Studies 9  Congenital Anomalies and Genetic 
on Rodent Models of Aganglionosis .... 54 Associations in Hirschsprung’s Disease ..... 115
4.6 Molecular Genetics ................... 55 S.W. Moore 
4.7 Contribution of Animal Models
to Theories as to the Cause 9.1 Introduction ........................ 115
of Aganglionosis ...................... 57 9.2 Etiology of HSCR .................... 115
4.8 Summary ............................ 58 9.3 Overview of Associated Anomalies
in HSCR ............................ 116
9.4 Gene-related Associations of HSCR ... 118
5  The Molecular Genetics  9.5 Significant Clinical Associations
of Hirschsprung’s Disease ................... 63 of HSCR ........................... 119
F. Lantieri, P. Griseri, J. Amiel, G. Martucciello,  9.6 Other Less Common Associations
I. Ceccherini, G. Romeo and S. Lyonnet with HSCR .......................... 124
5.1 Epidemiology and Genetics of HSCR ... 63
5.2 The RET Protooncogene .............. 64 10 Enterocolitis Complicating  
5.3 Other Genes Involved in HSCR Hirschsprung’s Disease .................... 133
Pathogenesis ......................... 65 F. Murphy, M. Menezes and P. Puri
5.4 Genetic Analysis to Identify Other
HSCR Loci ........................... 71 10.1 Introduction ........................ 133
5.5 Additional Contribution of the RET 10.2 Pathogenesis ........................ 133
Gene: SNPs and Haplotypes ........... 72 10.3 Theories of Pathogenesis ............. 134
5.6 Genetic Counseling ................... 73 10.4 Microbiology ....................... 137
10.5 Pathology ........................... 137
10.6 Risk Factors for Enterocolitis ......... 137
6  Normal Colonic Motor Function  10.7 Clinical Presentation and Diagnosis ... 138
and Relevant Structure ..................... 79 10.8 Treatment .......................... 140
J. Christensen 10.9 Prognosis ........................... 141
6.1 Introduction ......................... 79
6.2 Morphology ......................... 80 11 Diagnosis of Hirschsprung’s Disease 
6.3 Motor Functions of the Large Intestine 86 and Allied Disorders ...................... 145
J. Kelleher and N. Blake
7  Pathophysiology of Hirschsprung’s Disease .. 95 11.1 Radiological Diagnosis ............... 145
P. Puri and S. Montedonico 11.2 Initial Radiographs .................. 145
11.3 Differential Diagnosis ................ 146
7.1 Introduction ......................... 95 11.4 Enema Technique ................... 146
7.2 Organization of the Gut ............... 95 11.5 Enema Findings ..................... 148
7.3 Motility of the Gut .................... 98 11.6 Enterocolitis ........................ 149
Contents I
11.7 Postoperative Examinations .......... 149 14.3 Tissue Preparation for NADPH-
11.8 Intestinal Neuronal Dysplasia ........ 151 Diaphorase Histochemistry .......... 200
14.4 Whole-Mount Preparation Technique 200
14.5 NADPH-Diaphorase Histochemistry .. 200
12 Functional Diagnosis ...................... 153
A.M. Holschneider and I. Steinwegs
15 Immunohistochemical Studies ............. 207
12.1 Anorectal Motility ................... 153 U. Rolle and P. Puri
12.2 Physiology of the Internal Anal
Sphincter ........................... 155 15.1 Introduction ........................ 207
12.3 Comparison of the Internal Anal 15.2 General Markers .................... 209
Sphincter and the Rectum ............ 156 15.3 Cholinergic Markers ................. 212
12.4 Electromanometry .................. 157 15.4 (Nor)Adrenergic markers
12.5 Pathological Electromanometric (Tyrosine Hydroxylase/Dopamine
Criteria ............................. 166 β-Hydroxylase) ...................... 213
12.6 Potential Electromanometric Errors ... 171 15.5 Non-adrenergic Non-cholinergic
12.7 Accuracy of Electromanometry ....... 173 Markers ............................ 213
12.8 Anorectal Manovolumetry ........... 174 15.6 Neuropeptides ...................... 214
12.9 Electromyography ................... 174 15.7 Markers of Neuron-supporting Cells .. 215
12.10 Endosonography .................... 175 15.8 Synaptic Markers .................... 215
12.11 Transit-time studies ................. 175 15.9 Specific Staining of Hypertrophic Nerve
12.12 Conclusions ......................... 180 Fibers in HD ........................ 216
15.10 Diagnostic and Clinical Use:
Recommendations for Diagnosis ...... 216
13 Histopathological Diagnosis  
and Differential Diagnosis  
of Hirschsprung’s Disease .................. 185 16 Electron Microscopic Studies 
W. Meier-Ruge and E. Bruder of Hirschsprung’s Disease .................. 221
T. Wedel, H.-J. Krammer and A.M. Holschneider
13.1 Introduction ........................ 185
13.2 Hirschsprung’s Disease ............... 185 16.1 Introduction ........................ 221
13.3 Ultrashort Hirschsprung’s Disease 16.2 Ultrastructural Features of Intestinal
(UHD) ............................. 187 Aganglionosis ....................... 221
13.4 Total Aganglionosis of the Colon ..... 187 16.3 Pathogenetic Implications ............ 226
13.5 Hypoganglionosis of the Colon ....... 188
13.6 Immaturity of the Submucous
and Myenteric Plexus ................ 188 17 Intestinal Neuronal Malformations (IND): 
13.7 Intestinal Neuronal Dysplasia Clinical Experience and Treatment ......... 229
Type B (IND B) ..................... 189 A. M. Holschneider, P. Puri,  
13.8 Intestinal Neuronal Dysplasia L. H. Homrighausen, and W. Meier-Ruge
Type A (IND A) ..................... 191
13.9 Hypoplasia of Nerve Cells 17.1 Introduction ........................ 229
in the Submucous and Myenteric 17.2 Genetic Observations ................ 229
Plexus (Hypoplastic Dysganglionic 17.3 Occurrence ......................... 230
Oligoneuronal Hypoganglionosis) .... 191 17.4 Classification ........................ 231
13.10 Desmosis of the Colon ............... 193 17.5 Symptoms .......................... 232
13.11 Pathogenesis of Hirschsprung’s Disease 17.6 Incidence ........................... 233
and Related Disorders ............... 194 17.7 Biopsy Technique .................... 234
13.12 Artifacts and Pitfalls in the Enzyme 17.8 Diagnostic Criteria .................. 235
Histochemical Technique ............ 194 17.9 Newer Staining Techniques ........... 236
17.10 Age ................................ 237
17.11 Correlation Between Histological
14 NADPH-Diaphorase Histochemistry ....... 199 Findings and Clinical Symptoms ...... 237
U. Rolle and P. Puri 17.12 Maturation and Apoptosis ............ 238
17.13 Association Between IND and HD .... 238
14.1 Introduction ........................ 199 17.14 Management ........................ 244
14.2 Nitric Oxide and NADPH-Diaphorase 199 17.15 Conclusion: Is IND a Real Disease? ... 247