PDF herunterladen
Eur J Pediatr Surg 2008; 18(3): 140-149
DOI: 10.1055/s-2008-1038625
Review Article

© Georg Thieme Verlag KG Stuttgart · New York

Hirschsprung's Disease, One of the Most Difficult Diagnoses in Pediatric Surgery: A Review of the Problems from Clinical Practice to the Bench

G. Martucciello1
  • 1Paediatric Surgery Department, Scientific Inst. (IRCCS) Policlinico San Matteo, Pavia, Italy
Weitere Informationen

Publikationsverlauf

received March 3, 2008

accepted after revision March 16, 2008

Publikationsdatum:
21. Mai 2008 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Abstract

Purpose: The diagnosis of Hirschsprung's disease (HSCR) should take place early in the neonatal period, because without an effective diagnosis and appropriate treatment, a considerable proportion of infants will go on to develop serious complications such as acute enterocolitis or toxic megacolon. Because no more than 10 % of HSCR cases have a late presentation with classical chronic constipation and megacolon, the clinician has to make a difficult, early diagnosis, which is the crux of the clinical problem. The aim of this review paper is to present all tools currently available to make a clear HSCR diagnosis and to discuss the problems facing the clinician and the pediatric surgeon in the correct identification of HSCR and of other intestinal dysganglionoses. Methods: Based on the current state of knowledge and 24 years' personal experience in clinical practice and basic research in this field, I describe an algorithmic approach that enables clinicians and surgeons to rationalize and maximize the clarity of diagnosis through a complementary set of procedures and enzyme-histochemical reactions. Results: Two innovative techniques, added to the protocol in the last four years, are described: the lyophilized HSCR diagnostic kit, and the one-trocar transumbilical laparoscopic intestinal full-thickness biopsy technique (OTTLB). Conclusion: The rational, algorithmic diagnostic pathway proposed in this review paper aims to optimize every diagnosis by the stepwise application of a complementary set of procedures and enzyme-histochemical reactions as they become appropriate. In the interests of simplifying genetic molecular diagnosis, I suggest the following guidelines: 1) only in cases of total colonic aganglionosis (TCA) is it advisable to carry out full RET mutation screening (the mutation rate is up to 70 %); and 2) all HSCR patients should be tested only for standard MEN2A and MTC mutations. If these are present, the patients should be followed up carefully with proper surveillance and biochemical testing of other susceptible family members as they are at risk of developing neuroendocrine tumors.

Key words

Hirschsprung's disease (HSCR) - enteric nervous system (ENS) - intestinal neuronal dysplasia (IND) - histochemistry - lyophilization

References

  • 1 Amiel J, Lyonnet S. Hirschsprung disease, associated syndromes, and genetics: a review.  J Med Genet. 2001;  38 729-739
    CrossrefPubMedSuche in Google Scholar
  • 2 Angrist M, Bolk S, Thiel B, Puffenberger E G, Hofstra R M, Buys C H, Cass D T, Chakravarti A. Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung disease.  Hum Mol Genet. 1995;  4 821-830
    PubMedSuche in Google Scholar
  • 3 Attie T, Pelet A, Edery P, Eng C, Mulligan L M, Amiel J, Boutrand L, Beldjord C, Nihoul-Fékété C, Munnich A. Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease.  Hum Mol Genet. 1995;  4 1381-1386
    PubMedSuche in Google Scholar
  • 4 Badner J A, Sieber W K, Garver K L, Chakravarti A. A genetic study of Hirschsprung disease.  AM J Hum Genet. 1990;  46 568-580
    PubMedSuche in Google Scholar
  • 5 Bolk S, Pelet A, Hofstra R M, Angrist M, Salomon R, Croaker D, Buys C H, Lyonnet S, Chakravarti A. A human model for multigenic inheritance: phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locus.  Proc Natl Acad Sci USA. 2000;  97 268-273
    CrossrefPubMedSuche in Google Scholar
  • 6 Borchard F, Meier-Ruge W, Wiebecke B, Briner J, Müntefering H, Födisch H F, Holschneider A M, Schmidt A, Enck P, Stolte M. Disorders of the innervation of the large intestine - classification and diagnosis. Results of a consensus conference of the Society of Gastroenteropathology 1 December 1990 in Frankfurt/Main.  Pathologe. 1991;  12 171-174
    PubMedSuche in Google Scholar
  • 7 Borrego S, Ruiz A, Saez M E, Gimm O, Gao X, López-Alonso M, Hernández A, Wright F A, Antiñolo G, Eng C. RET genotypes comprising specific haplotypes of polymorphic variants predispose to isolated Hirschsprung disease.  J Med Genet. 2000;  37 572-578
    Suche in Google Scholar
  • 8 Brizzolara A, Favre A, Schäfer K H, Michelazzi A, Sanguineti M, Martucciello G, Jasonni V. Mouse-isolated plexus differentiates neural crest precursors into enteric neuroblasts.  Eur J Pediatr Surg. 2002;  12 391-396
    Thieme ConnectPubMedSuche in Google Scholar
  • 9 Brizzolara A, Torre M, Favre A, Pini Prato A, Bocciardi R, Martucciello G. Histochemical study of Dom mouse: a model for Waardenburg-Hirschsprung's phenotype.  J Pediatr Surg. 2004;  39 1098-1103
    CrossrefPubMedSuche in Google Scholar
  • 10 Bruder E, Meier-Ruge W A. Intestinal neuronal dysplasia type B: how do we understand it today?.  Pathologe. 2007;  28 137-142
    CrossrefPubMedSuche in Google Scholar
  • 11 Bruder E, Terracciano L M, Passarge E, Meier-Ruge W A. Enzyme histochemistry of classical and ultrashort Hirschsprung's disease.  Pathologe. 2007;  28 105-112
    CrossrefPubMedSuche in Google Scholar
  • 12 Chakravarti A, Lyonnet S. Hirschsprung disease. Scriver CR, Beaudet AL, Valle D, Sly W The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York; McGraw-Hill 2000: 6203-6230
    Suche in Google Scholar
  • 13 Dasgupta R, Langer J C. Hirschsprung disease.  Curr Probl Surg. 2004;  41 942-988
    CrossrefPubMedSuche in Google Scholar
  • 14 Davis B J, Ornstein L. High resolution enzyme localisation with a new diazo reagent, “hexazonium pararosaniline”.  J Hist Cyt. 1959;  7 297
    PubMedSuche in Google Scholar
  • 15 de Lorijn F, Kremer L C, Reitsma J B, Benninga M A. Diagnostic tests in Hirschsprung disease: a systematic review.  J Pediatr Gastroenterol Nutr. 2006;  42 496-505
    CrossrefPubMedSuche in Google Scholar
  • 16 Deucher F, Nöthiger F. Surgical treatment of ulcerative colitis.  Chirurg. 1977;  48 563-568
    PubMedSuche in Google Scholar
  • 17 Dodero P, Martucciello G. Hirschsprung's disease: alpha-naphthyl-esterase activity in the enzyme-histochemical evaluation of the extent of the aganglionic segment during surgery.  Pediatr Surg Int. 1988;  4 269-274
    PubMedSuche in Google Scholar
  • 18 Dzienis-Koronkiewicz E, Debek W, Chyczewski L. Use of synaptophysin immunohistochemistry in intestinal mobility disorders.  Eur J Ped Surg. 2005;  15 392-398
    PubMedSuche in Google Scholar
  • 19 Ehrenpreis T. Hirschsprung's disease.  Am J Dig Dis. 1971;  16 1032-1052
    CrossrefPubMedSuche in Google Scholar
  • 20 Fadda B, Maier W A, Meier-Ruge W, Schärli A, Daum R. Neuronal intestinal dysplasia. Critical 10-years' analysis of clinical and biopsy diagnosis.  Z Kinderchir. 1983;  38 305-311
    PubMedSuche in Google Scholar
  • 21 Gabriel S B, Salomon R, Pelet A, Angrist M, Amiel J, Fornage M, Attié-Bitach T, Olson J M, Hofstra R, Buys C, Steffann J, Munnich A, Lyonnet S, Chakravarti A. Segregation at three loci explains familial and population risk in Hirschsprung disease.  Nat Genet. 2002;  31 89-93
    PubMedSuche in Google Scholar
  • 22 Georgeson K E. Laparoscopic-assisted total colectomy with pouch reconstruction.  Semin Pediatr Surg. 2002;  11 233-236
    CrossrefPubMedSuche in Google Scholar
  • 23 Grand R J, Homer D R. Approaches to inflammatory bowel disease in childhood and adolescence.  Pediatr Clin North Am. 1975;  22 835-850
    PubMedSuche in Google Scholar
  • 24 Griseri P, Pesce B, Patrone G, Osinga J, Puppo F, Sancandi M, Hofstra R, Romeo G, Ravazzolo R, Devoto M, Ceccherini I. A rare haplotype of the RET proto-oncogene is a risk-modifying allele in Hirschsprung disease.  Am J Hum Genet. 2002;  71 969-974
    CrossrefPubMedSuche in Google Scholar
  • 25 Griseri P, Sancandi M, Patrone G, Bocciardi R, Hofstra R, Ravazzolo R, Devoto M, Romeo G, Ceccherini I. A single-nucleotide polymorphic variant of the RET proto-oncogene is underrepresented in sporadic Hirschsprung disease.  Eur J Hum Genet. 2000;  8 721-724
    CrossrefPubMedSuche in Google Scholar
  • 26 Gunnarsdottir A, Wierup N, Larsoon L T, Kuharb M J, Ekblad E. CART-peptide immunoreactivity in enteric nerves in patients with Hirschspurng's disease.  Eur J Pediatric Surg. 2007;  17 184-189
    PubMedSuche in Google Scholar
  • 27 Holschneider A, Kunst M. Anal sphincter achalasia and ultrashort Hirschsprung's disease. Holschneider A, Puri P Hirschsprung's Disease and Allied Disorders. 3rd ed. Berlin, Heidelberg, New York; Springer 2008: 297-322
    Suche in Google Scholar
  • 28 Holschneider A, Steinwegs I. Functional diagnosis. Holschneider A, Puri P Hirschsprung's Disease and Allied Disorders. 3rd ed. Berlin, Heidelberg, New York; Springer 2008: 133-184
    Suche in Google Scholar
  • 29 Huntley C C, Shaffner L D, Challa V R, Lyerly A D. Histochemical diagnosis of Hirschsprung disease.  Pediatric. 1982;  69 755-761
    PubMedSuche in Google Scholar
  • 30 Ito S, Iwashita T, Asai N, Murakami H, Iwata Y, Sobue G, Takahashi M. Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung's disease phenotype.  Cancer Res. 1997;  57 2870-2872
    PubMedSuche in Google Scholar
  • 31 Jasonni J, Pini Prato A, Martucciello G. Soave's extramucosal endorectal pull-through procedure. Holschneider A, Puri P Hirschsprung's Disease and Allied Disorders. 3rd ed. Berlin, Heidelberg, New York; Springer 2008: 337-348
    Suche in Google Scholar
  • 32 Kaiser G, Bettex M. Terminology and classification. Holschneider A Hirschsprung's Disease. 1st ed. Stuttgart; Thieme Stratton 1982: 42-47
    Suche in Google Scholar
  • 33 Kapur R P. Can we stop looking? Immunohistochemistry and the diagnosis of Hirschsprung disease.  Am J Clin Pathol. 2006;  126 9-12
    CrossrefPubMedSuche in Google Scholar
  • 34 Karnovsky M J, Roots L. A “direct colorino” thiocholine method for cholinesterases.  J Histochem Cytochem. 1964;  12 219-221
    CrossrefPubMedSuche in Google Scholar
  • 35 Kawahara H, Kubota A, Hasegawa T, Okuyama H, Ueno T, Watanabe T, Morishita Y, Saka R, Fukuzawa M. Anorectal sleeve micromanometry for the diagnosis of Hirschsprung's disease in newborns.  J Pediatr Surg. 2007;  42 2075-2079
    CrossrefPubMedSuche in Google Scholar
  • 36 Kelleher J, Blake N. Diagnosis of Hirschsprung's disease and allied disorders. Holschneider A, Puri P Hirschsprung's Disease and Allied Disorders. 3rd ed. Berlin, Heidelberg, New York; Springer 2008: 145-151
    Suche in Google Scholar
  • 37 Langer B, Thomson S. Hirschsprung's disease; nine years' experience at the Hospital for Sick Children, Toronto.  Can J Surg. 1959;  2 123-130
    PubMedSuche in Google Scholar
  • 38 Lantieri F, Griseri P, Amiel J, Martucciello G, Ceccherini I, Romeo G, Lyonnet S. The molecular genetics of Hirschsprung disease. Holschneider A, Puri P Hirschsprung's Disease and Allied Disorders. 3rd ed. Berlin, Heidelberg, New York; Springer 2008: 63-78
    Suche in Google Scholar
  • 39 Lillie J G, Chrispin A R. Hirschsprung's disease in the neonate.  Ann Radiol. 1971;  14 265-270
    PubMedSuche in Google Scholar
  • 40 Martucciello G, Bicocchi M P, Dodero P, Lerone M, Silengo Cirillo M, Puliti A, Gimelli G, Romeo G, Jasonni V. Total colonic aganglionosis associated with interstitial deletion of the long arm of chromosome 10.  Pediatr Surg. 1992;  7 308-310
    PubMedSuche in Google Scholar
  • 41 Martucciello G, Brizzolara A, Favre A, Lomabardi L, Bocciardi R, Sanguinatti M, Pini Prato A. Neural crest neuroblast can colonize aganglionic and ganglionic gut in vivo.  Eur J Ped Surg. 2007;  17 34-40
    PubMedSuche in Google Scholar
  • 42 Martucciello G, Ceccherini I, Lerone M, Jasonni V. Pathogenesis of Hirschsprung's disease.  J Pediatr Surg. 2000;  35 1017-1025
    CrossrefPubMedSuche in Google Scholar
  • 43 Martucciello G, Luinetti O, Romano P, Magrini U. Molecular biology, basic research and diagnosis of Hirschsprung's disease.  Pathologe. 2007;  28 119-124
    CrossrefPubMedSuche in Google Scholar
  • 44 Martucciello G, Pini Prato A, Puri P, Holschneider A M, Meier-Ruge W, Jasonni V, Tovar J A, Grosfeld J L. Controversies concerning diagnostic guidelines for anomalies of the enteric nervous system: a report from the fourth international symposium on Hirschsprung's disease and related neurocristopathies.  J Pediatr Surg. 2005;  40 1527-1531
    CrossrefPubMedSuche in Google Scholar
  • 45 Martucciello G, Tam P. RET protein in human fetal development and in Hirschsprung disease. Holschneider A, Puri P Hirschsprung's Disease and Allied Disorders. 2nd ed. Amsterdam; Harwood 2000: 81-88
    Suche in Google Scholar
  • 46 Meier-Ruge W A. Das Megacolon, seine Diagnose und Pathophysiologie.  Virchows Arch Abt A. 1968;  344 67-85
    PubMedSuche in Google Scholar
  • 47 Meier-Ruge W A, Bruder E. Pathology of chronic constipation in pediatric and adult coloproctology.  Karger AG, Basel (Switzerland): Pathobiology. 2005;  72 1-106
    PubMedSuche in Google Scholar
  • 48 Meier-Ruge W A, Bruder E. The morphological characteristics of aplastic and atrophic desmosis of the intestine.  Pathologe. 2007;  28 149-154
    CrossrefPubMedSuche in Google Scholar
  • 49 Meier-Ruge W, Lutterbeck P M, Herzog B, Morger R, Moser R, Schärli A. Acetylcholinesterase activity in suction biopsies of the rectum in the diagnosis of Hirschsprung's disease.  J Pediatr Surg. 1972;  7 11-17
    CrossrefPubMedSuche in Google Scholar
  • 50 Meijers J H, Van der Sanden M P, Tibboel D. et al . Colonization characteristics of enteric neural crest cells: embryological aspects of Hirschsprung's disease.  J Pediatr Surg. 1992;  27 811-814
    CrossrefPubMedSuche in Google Scholar
  • 51 Mulligan L M, Eng C, Attie T, Lyonnet S, Marsh D J, Hyland V J, Robinson B G, Frilling A, Verellen-Dumoulin C, Safar A. Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene.  Hum Mol Genet. 1994;  3 2163-2167
    PubMedSuche in Google Scholar
  • 52 Mulligan L M, Ponder B A. Genetic basis of endocrine disease: multiple endocrine neoplasia type 2.  J Clin Endocrinol Metab. 1995;  80 1989-1995
    CrossrefPubMedSuche in Google Scholar
  • 53 Murphy F, Menezes M, Puri P. Enterocolitis complicating Hirschsprung's disease. Holschneider A, Puri P Hirschsprung's Disease and Allied Disorders. 3rd ed. Berlin, Heidelberg, New York; Springer 2008: 133-143
    Suche in Google Scholar
  • 54 Nachlas M M, Tsou K C, Souza E, Chery C S. Cytochemical demonstration of succinic dehydrogenase by the use of a new p-nitrophenyl substituted ditetrazole.  J Histochem Cytochem. 1957;  5 420-436
    CrossrefPubMedSuche in Google Scholar
  • 55 Nixon H. Hirschsprung's disease in the newborn. Holschneider A Hirschsprung's Disease. 1st ed. Stuttgart; Thieme Stratton 1982: 103-113
    Suche in Google Scholar
  • 56 Noblett H R. A rectal suction biopsy tube for use in the diagnosis of Hirschsprung's disease.  J Pediatr Surg. 1969;  4 406-409
    CrossrefPubMedSuche in Google Scholar
  • 57 Pini Prato A, Martucciello G, Jasonni V. Solo-RBT: a new instrument for rectal suction biopsies in the diagnosis of Hirschsprung's disease.  J Pediatr Surg. 2001;  36 1364-1366
    CrossrefPubMedSuche in Google Scholar
  • 58 Pini-Prato A, Martucciello G, Jasonni V. Rectal suction biopsy in the diagnosis of intestinal dysganglionoses: 5-year experience with Solo-RBT in 389 patients.  J Pediatr Surg. 2006;  41 1043-1048
    CrossrefPubMedSuche in Google Scholar
  • 59 Puri P, Lake B D, Nixon H H, Mishalany H, Claireaux A E. Neuronal colonic dysplasia: an unusual association of Hirschsprung's disease.  J Pediatr Surg. 1977;  12 681-685
    CrossrefPubMedSuche in Google Scholar
  • 60 Puri P, Montedonico S. Hirschsprung's disease: clinical features. Holschneider A, Puri P Hirschsprung's Disease and Allied Disorders. 3rd ed. Berlin, Heidelberg, New York; Springer 2008: 106-113
    Suche in Google Scholar
  • 61 Ratcliffe E M, deSa D J, Dixon M F, Stead R H. Choline acetyltransferase (ChAT) immunoreactivity in paraffin sections of normal and diseased intestines.  J Histochem Cytochem. 1998;  46 1223-1231
    PubMedSuche in Google Scholar
  • 62 Rolle U, Puri P. Immunohistochemical studies. Holschneider A, Puri P Hirschsprung's Disease and Allied Disorders. 3rd ed. Berlin, Heidelberg, New York; Springer 2008: 207-220
    Suche in Google Scholar
  • 63 Romeo G, Ronchetto P, Luo Y, Barone V, Seri M, Ceccherini I, Pasini B, Bocciardi R, Lerone M, Kääriäinen H, Martuccuielo G. Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease.  Nature. 1994;  367 377-378
    CrossrefPubMedSuche in Google Scholar
  • 64 Schärli A F. Intestinal neuronal dysplasia.  Pediatr Surg Int. 1992;  7 2-7
    PubMedSuche in Google Scholar
  • 65 Schärli A F, Meier-Ruge W. Localized and disseminated forms of neuronal intestinal dysplasia mimicking Hirschsprung's disease.  J Pediatr Surg. 1981;  16 164-170
    PubMedSuche in Google Scholar
  • 66 Seri M, Yin L, Barone V, Bolino A, Celli I, Bocciardi R, Pasini B, Ceccherini I, Lerone M, Kristoffersson U, Larsson L T, Casasa J M, Cass D T, Abramowicz M J, Vanderwinden J M, Kravcenkiene I, Baric I, Silengo M, Martucciello G, Romeo G. Frequency of RET mutations in long- and short-segment Hirschsprung disease.  Hum Mutat. 1997;  9 243-249
    CrossrefPubMedSuche in Google Scholar
  • 67 Sieber W K. Hirschsprung's disease.  Curr Probl Surg. 1978;  15 1-76
    PubMedSuche in Google Scholar
  • 68 Sukotnic I, Bernshteyn A, Mogilner J G. The basic biology of apoptosis and its implications for pediatric surgery.  Eur J Ped Surg. 2005;  15 229-235
    PubMedSuche in Google Scholar
  • 69 Swenson O, Fisher J H. Hirschsprung's disease in the newborn.  Arch Surg. 1959;  79 987-993
    PubMedSuche in Google Scholar
  • 70 Swenson O, Sherman J O, Fisher J H. Diagnosis of congenital megacolon: an analysis of 501 patients.  J Pediatr Surg. 1973;  8 587-594
    CrossrefPubMedSuche in Google Scholar
  • 71 Tafazzoli K, Soost K, Wessel L, Wedel T. Topografic peculiarities of the submucous plexus in the human anorectum - consequences for histopathologic evaluation of rectal biopsies.  Eur J Pediatr Surg. 2005;  15 159-163
    Suche in Google Scholar
  • 72 Taguchi T, Suita S, Masumoto K, Nagasaki A. An abnormal distribution of C‐kit positive cells in the normoganglionic segment can predict a poor clinical outcome in patients with Hirschsprung's disease.  Eur J Pediatr Surg. 2005;  15 153-158
    Thieme ConnectPubMedSuche in Google Scholar
  • 73 Tam P K, Gould S J, Martucciello G, Biddolph S, Takahashi M, Jasonni V. Ret protein in the human fetal rectum.  J Pediatr Surg. 1996;  31 568-571
    CrossrefPubMedSuche in Google Scholar
  • 74 Tobon F, Schuster M M. Megacolon: special diagnostic and therapeutic features.  Johns Hopkins Med J. 1974;  135 91-105
    PubMedSuche in Google Scholar
  • 75 Werbeloff L, Novis B, Bank S, Marks I N. Radiology of acute toxic megacolon.  S Afr Med J. 1974;  48 912-914
    PubMedSuche in Google Scholar
  • 76 Yamataka A, Ohshiro K, Kobayashi H, Fujiwara T, Sunagawa M, Miyano T. Intestinal pacemaker C‐KIT+ cells and synapses in allied Hirschsprung's disorders.  J Pediatr Surg. 1997;  32 1069-1074
    CrossrefPubMedSuche in Google Scholar
  • 77 Zuelzer W W, Wilson J L. Functional intestinal obstruction on a congenital neurogenic basis in infancy.  Am J Dis Childh. 1948;  75 40-64
    PubMedSuche in Google Scholar

Associate Prof. M.D., Surgeon-in-Chief Giuseppe Martucciello

Paediatric Surgery Department
Scientific Inst. (IRCCS) Policlinico San Matteo

Via le Golgi 19

27100 Pavia

Italy

eMail: martucciello@yahoo.com