This action might not be possible to undo. Are you sure you want to continue?
Hirschsprung disease, associated syndromes, and genetics: a review
Jeanne Amiel, Stanislas Lyonnet
Abstract Hirschsprung disease (HSCR, aganglionic megacolon) is the main genetic cause of functional intestinal obstruction with an incidence of 1/5000 live births. This developmental disorder is a neurocristopathy and is characterised by the absence of the enteric ganglia along a variable length of the intestine. In the last decades, the development of surgical approaches has dramatically decreased mortality and morbidity, which has allowed the emergence of familial cases. HSCR appeared to be a multifactorial malformation with low, sex dependent penetrance and variable expression according to the length of the aganglionic segment, suggesting the involvement of one or more gene(s) with low penetrance. So far, eight genes have been found to be involved in HSCR. This frequent congenital malformation now stands as a model for genetic disorders with complex patterns of inheritance.
(J Med Genet 2001;38:729–739) Keywords: Hirschsprung disease; aganglionic megacolon; genetics
additional congenital anomalies in 18% of cases.8–13 In the latter group of patients, some monogenic syndromes can be recognised. Isolated HSCR appears to be a multifactorial malformation with low, sex dependent penetrance, variable expression according to the length of the aganglionic segment, and suggesting the involvement of one or more gene(s) with low penetrance.5 14 These parameters must be taken into account for accurate evaluation of the recurrence risk in relatives. Segregation analyses suggested an oligogenic mode of inheritance in isolated HSCR.14 With a relative risk as high as 200, HSCR is an excellent model for the approach to common multifactorial diseases. So far, genetic heterogeneity in HSCR has been shown with eight speciﬁc genes involved. The major susceptibility gene is RET, which is also involved in multiple endocrine neoplasia type 2 (MEN 2). The identiﬁcation of modiﬁer genes is currently under way. The aim of this paper is to review the clinical data on syndromic HSCR and the molecular ﬁndings over the last 10 years. Deﬁnition and classiﬁcation HSCR is a congenital malformation of the hindgut characterised by the absence of parasympathetic intrinsic ganglion cells in the submucosal and myenteric plexuses.2 It is regarded as the consequence of the premature arrest of the craniocaudal migration of vagal neural crest cells in the hindgut between the ﬁfth and twelfth week of gestation to form the enteric nervous system (ENS) and is therefore regarded as a neurocristopathy.6 15 While the internal anal sphincter is the constant inferior limit, patients can be classiﬁed as short segment HSCR (S-HSCR, 80% of cases) when the aganglionic segment does not extend beyond the upper sigmoid, and long segment HSCR (L-HSCR, 20% of cases) when aganglionosis extends proximal to the sigmoid. Four HSCR variants have been reported: (1) total colonic aganglionosis (TCA, 3-8% of cases),16 (2) total intestinal HSCR when the whole bowel is involved,16 (3) ultra short segment HSCR involving the distal rectum below the pelvic ﬂoor and the anus,17 and (4) suspended HSCR, a controversial condition, where a portion of the colon is aganglionic above a normal distal segment.
Département de Génétique, Unité INSERM U-393, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75743 Paris Cedex 15, France J Amiel S Lyonnet
Correspondence to: Dr Lyonnet, firstname.lastname@example.org
Harald Hirschsprung ﬁrst described in 1888 two unrelated boys who died from chronic severe constipation with abdominal distension resulting in congenital megacolon.1 The absence of intramural ganglion cells of the myenteric and submucosal plexuses (Auerbach’s and Meissner’s plexuses, respectively) downstream from the dilated part of the colon was considered to be the cause of the disease in the 1940s.2 This allowed simple and reliable diagnostic conﬁrmation from rectal suction biopsies using histochemical staining for acetylcholinesterase (AchE).3 In 1948, Swenson and Bill developed a surgical procedure4 and the survival of patients uncovered familial transmission of HSCR.5 In 1973, Bolande6 proposed the term neurocristopathy for syndromes or tumours involving neural crest (NC) cells. HSCR resulting from an anomaly of the enteric nervous system (ENS) of NC origin is therefore regarded as a neurocristopathy.6 7 HSCR occurs as an isolated trait in 70% of patients, is associated with a chromosomal abnormality in 12% of cases, and with
trisomy 21 being by far the most frequent (>90%). a distended small bowel and proximal colon with an empty rectum are common ﬁndings.75 Dominant 52:40 17/13 33/9 S-HSCR 81 5. Lyonnet *Recurrence risk are given for male/female sibs respectively. involving 2-10% of ascertained HSCR cases.5 Multigenic or recessive 17:4 5/1 5/3 Amiel. The transition zone represents the site where the narrow aganglionic bowel joins the dilated ganglionic bowel. Free trisomy 21 (Down syndrome) is by far the most frequent. chronic abdominal distension. Some patients are diagnosed later in infancy or in adulthood with severe constipation. the diagnosis of HSCR is made in the newborn period13 owing to intestinal obstruction with the following features: (1) failure to pass meconium within the ﬁrst 48 hours of life. mutations in genes predisposing to HSCR. The classical image is a dilated proximal colon with the aganglionic cone narrowing towards the distal gut. African-Americans.jmedgenet. have been found in only three patients with Down syndrome and HSCR.31 32 Some chromosomal interstitial deletions reported in combination with HSCR have been important for the identiﬁcation of HSCR predisposing genes. Furthermore. both the unbalanced sex ratio (5. Chromosomal anomalies A large number of chromosomal anomalies have been described in HSCR patients.13 S-HSCR is far more frequent than L-HSCR (80% and 20%.8 per 10 000 live births in Caucasians. (3) ENS anomalies grouped together as chronic intestinal pseudo-obstruction syndromes.5. respectively). Overexpression of genes on chromosome 21 predisposing to HSCR has been hypothesised and a susceptibility gene mapping to 21q22 postulated in a Mennonite kindred.24 Long term complications include chronic constipation (10-15%) and soiling. After careful preoperative management.13 14 HSCR occurs as an isolated trait in 70% of cases. Otherwise. and GDNF.5 However. namely: (1) meconium ileus resulting from cystic ﬁbrosis.com .27 Mortality is under 6% since the 1980s and may be related to short term complications or caused by the associated malformations. On abdominal x ray. and (4) neonatal enterocolitis. intestinal malrotation.8 10 There is a sex bias with a preponderance of aVected males and a sex ratio of 4/1.730 Table 1 Epidemiology and recurrence risk ﬁgures in HSCR14 L-HSCR % probands Sex ratio (male:female) Genetic model Penetrance (%) (male:female) Recurrence risk to sibs* (%) Male proband Female proband 19 1. Since the initial protocol of Swenson described in 1948. the treatment of children with TCA is still hazardous.5 male:female) and the predominance of S-HSCR are even greater than in isolated HSCR.2 interstitial deletion observed in a few patients with www. isolated or occasionally associated with HSCR. namely RET. and (4) functional intestinal obstruction resulting from maternal infection. and failure to thrive.20 Suction rectal biopsy conﬁrms the diagnosis in most cases. unexplained perforation of the caecum or appendix should make the diagnosis be considered. the incidence varies signiﬁcantly among ethnic groups (1. the principle is to place the normal bowel at the anus and to release the tonic contraction of the internal anal sphincter. A chromosomal abnormality is associated with it in 12% of cases. extramucosal serial biopsies will be required at laparotomy to deﬁne the proximal limit of the aganglionic segment. On a plain x ray taken later. DiVerential diagnosis Other causes of intestinal obstruction should be considered when abdominal distension and failure to pass meconium occur in a newborn infant. 2.19 The reliability of this test becomes excellent from day 12 after birth when the normal rectoenteric reﬂex is present. (2) intestinal malformations such as lower ileal and colonic atresia. Fistula or stenosis of the anastomosis and enterocolitis are the main short term complications. although a rare presentation. (3) vomiting.11 12 The higher rate of associated anomalies in familial cases than in isolated cases (39% versus 21%) strongly suggests syndromes with Mendelian inheritance. On barium enema a small rectum with uncoordinated contractions is seen. such as the Soave and Duhamel procedures.28 29 Epidemiology The incidence of HSCR is estimated at 1/5000 live births. and craniofacial anomalies. maternal intoxication. delayed barium evacuation is observed.22 23 A one stage procedure is possible when diagnosis is made early. or congenital hypothyroidism.5-10.18 Finally. cleft palate. polydactyly. cardiac septal defects. namely (1) 10q11. and 2. a primary colostomy is required.30 However.21 but a full thickness rectal biopsy is needed for diagnosis of HSCR. EDNRB. Hitherto.25 26 Laparoscopic techniques have recently been proposed in HSCR surgery. (2) abdominal distension that is relieved by rectal stimulation or enemas. respectively). Treatment and prognosis The treatment of HSCR is surgical.25 However.12 Assessment of all HSCR patients should include a careful evaluation for recognisable syndromes by a trained dysmorphologist.1. The ones occurring at a frequency above that expected by chance include gastrointestinal malformation. Associated congenital anomalies are found in 18% of HSCR patients.4 a series of operative approaches have been developed. respectively. Clinical features and diagnosis In most cases. Anorectal manometry shows absence of relaxation of the internal sphincter in response to rectal distension.14 Interestingly.5 9–13 In these cases. and Asians. these data were not conﬁrmed in other populations. vomiting. the male:female ratio is signiﬁcantly higher for S-HSCR than for L-HSCR (table 1). before colonic dilatation. or duplication.
craniofacial. and pigmentary tissues.com . postaxial polydactyly Hydrometrocolpos. (3) occasional association with recognisable syndromes. microcephaly. and Table 3 Syndromes associated with HSCR (reprinted and adapted from Scriver CM et al. Syndromes and associated anomalies Both the recognition of known entities and the delineation of novel ones including HSCR as a feature are of importance for disease prognosis. congenital heart defect Growth retardation. HSCR* MCA/MR Cat eye syndrome Number of reports 2 to 10% of HSCR cases 2 cases 7 cases 3 cases 4 cases 4 cases Gene ? RET EDNRB SIP1 ? ? ? 731 Chromosome Tri 21 Del 10q11 Del 13q22 Del 2q22-q23 Del 17q21 Dup 17q21-q23 Tri 22pter-q11 References 5. Ear/eye anomalies. Chap 251. and 20p deletion each have been observed once with HSCR. L-HSCR Mental retardation. epilepsy. unilateral renal agenesis. 92 89 96 97 99. growth retardation. deafness Postaxial polydactyly. dysmorphic features Preaxial polydactyly. coloboma. S-HSCR. metaphyseal dysplasia.33 34 leading to the mapping and identiﬁcation of the ﬁrst gene for HSCR (RET). Skeletal malformation. dysmorphic facial features Polydactyly. partial duplication of chromosome 2q. Werner type HSCR occasionally associated Bardet-Biedl and/or KauVman-McKusick Smith-Lemli-Opitz Cartilage-hair hypoplasia HSCR rarely associated Fukuyama congenital muscular dystrophy Clayton-Smith Kaplan Okamoto Miscellaneous associations Pallister-Hall (CAVE) Fryns Aarskog Jeune asphyxiating thoracic dystrophy Frontonasal dysplasia Osteopetrosis Goldenhar Lesch-Nyhan Rubinstein-Taybi Toriello-Carey SEMDJL 209900 236700 270400 250250 253800 258840 304100 308840 140510 229850 100050 208500 136760 164210 308000 180849 217980 271640 79 82 83 84 85 86 87 170 91. accurate genetic counselling.38–40 leading to the identiﬁcation of the SIP1 gene (SMAD interacting protein 1). 71 43–50 BRESHEK Mesomelic dysplasia. 34 35–37 38–41 *Both S-HSCR and L-HSCR have been observed. corpus callosum agenesis References 53–57 60 61 62. 5. 100 101 102 103 www.7 Neurocristopathies encompass tumours. congenital central hypoventilation. eds. dysmorphic features. 2–3 toes syndactyly. ventricular septal defect Hypoplasia of distal phalanges and nails. endocrine and paraendocrine. hypotonia. and (4) miscellaneous observations (table 3). mental retardation.1 interstitial deletion in patients with S-HSCR encompassing a second gene (EDNRB)35–37.1-32. MR. Syndromes associated with HSCR can be classiﬁed as: (1) pleiotropic neurocristopathies. cleft palate. malformations. and search for candidate genes. dysmorphic features. “The metabolic and molecular bases of inherited diseases” 8th ed. postaxial polydactyly. 9–13 33. hypopigmentation of the skin and retina Patchy hypopigmentation of the skin Congenital central hypoventilation Medullary thyroid carcinoma. obesity. conotruncal heart.5 male:female sex ratio Mental retardation. seizures Dysmorphic features.39 L-HSCR or TCA. Agenesis of corpus callosum. S-HSCR Postnatal growth retardation and microcephaly. microcephaly. laryngeal anomalies Brachydactyly type D Brain abnormalities. hypospadias.) Syndromes Neurocristopathy syndromes WS4 (Shah-Waardenburg) Yemenite deaf-blind-hypopigmentation BADS Piebaldism Haddad MEN2A Riley-Day HSCR mandatory Goldberg-Shprintzen HSCR with limbs anomalies MIM 277580 601706 227010 172800 209880 171400 223900 235730 235740 235750 235760 604211 306980 Key features Pigmentary anomalies (white forelock. NEUROCRISTOPATHIES The NC is a transient and multipotent embryonic structure that gives rise to neuronal. MEN 2. hyperplasia of the parathyroid Autonomic nervous system anomalies Cleft palate. (3) 2q22-23 interstitial deletion syndrome in patients with HSCR (table 2). Ectodermal dysplasia. (2) 13q22. phaeochromocytoma. mental retardation. conotruncal heart defects. ptosis. hypogenitalism. 63 70. nystagmus). muscle weakness Hydrocephalus. mosaic trisomy 8. mild mental retardation. associated syndromes. adducted thumbs.5 to 10. pigmentary anomalies Hearing loss. patchy hypopigmentation).41 Rarer chromosomal anomalies reported in combination with HSCR are summarised in table 2. polydactyly Pigmentary retinopathy. polymicrogyria. Kidney dysplasia Mesomelia. ichthyosis.jmedgenet. (2) syndromes with HSCR as a mandatory feature. mental retardation. Hirschsprung disease. DiGeorge syndrome. tetrasomy 9p. heart defect. hypoplastic toes and nails. hydrocephalus. deafness Hearing loss. Retardation. hypertelorism. dysmorphic features Short limb dwarﬁsm. XXY chromosomal constitution. iris hypoplasia. and single or multifocal abnormalities of tissues mentioned above in various combinations. eye anomalies (microcornea. and genetics Table 2 Recurrent chromosomal anomalies with HSCR as a feature Key features Down syndrome. immunodeﬁciency Muscular dystrophy. New York: McGraw-Hill: 6231-55. Several patients presenting the same pattern of congenital malformations and normal chromosomes have been reported.Hirschsprung disease.
and the sex ratio is equal. should be screened for RET exon 10 and 11 mutations to rule out cancer predisposition (3/160 cases in our series. these families present a germline RET mutation of the MEN 2A or FMTC type (see below). iris coloboma.52 The combination of HSCR with WS deﬁnes the WS4 type (ShahWaardenburg syndrome. and demyelinating peripheral and central neuropathies. microcephaly and mental retardation with or without facial dysmorphic features (hypertelorism.732 Amiel.44–50 This raises the question of whether all subjects with HSCR. In addition to MTC and phaeochromocytoma.65–68 CCHS may be a polygenic disorder with a major locus being involved.64 Congenital central hypoventilation syndrome (CCHS. SYNDROMES WITH HSCR AS A MANDATORY FEATURE Goldberg-Shprintzen syndrome (MIM 235730) This rare. Waardenburg syndromes (WS) and related pigmentary anomalies WS. hypotonia. phaeochromocytoma (50% of cases). unilateral renal agenesis.65 CCHS patients often present symptoms resulting from a broader dysfunction of the autonomic nervous system and neural crest cell derived tumours have also been observed. MEN type 2A.42 Germline missense mutations of the RET gene have been identiﬁed in MEN 2A. hypoplasia of the distal phalanges and nails. (3) HSCR.jmedgenet. patients with a SIP1 gene mutation have a diVerent condition. CCHS is a rare.78 The signiﬁcance of these associations is not yet established. cleft palate. C611R. 70% by the age of 70 years). cleft palate. hypertelorism. synophrys.43–50 Interestingly. Other occasional associations reported so far include cleft lip with or without cleft palate.75 76 neural tube defects (myelomeningocele). These are: (1) HSCR with polydactyly.65 Haddad syndrome (MIM 209880) is deﬁned by the combination of CCHS with HSCR and represents 14-20% of CCHS patients.70 71 In these cases. and mild dysmorphic features (MIM www. Both FMTC and MEN 2A can be associated with HSCR in some families. prominent nose. (2) HSCR.80 81 In our opinion. MIM 277580).77 and neuroﬁbromatosis type 1. MIM 193510). and hyperplasia of the parathyroid glands (15-35%). sparse hair). MEN 2A is deﬁned by an age related predisposition to medullary thyroid carcinoma (MTC. and mental retardation may be variants of this syndrome. A SOX10 mutation has been reported in one of these families60. L-HSCR (including TCA) is by far the most frequent. MIM 227010) with TCA-HSCR reported in one case61. and ventricular septal defects (MIM 235750)83.72 73 a GDNF mutation inherited from a healthy mother in a CCHS patient. HSCR with limb anomalies A series of rare syndromes with HSCR and distal limb anomalies (polydactyly or hypoplasia) have been reported.72 and an EDN3 mutation in a CCHS patient. MIM 148820. an autosomal dominant condition. Although it could have arisen by chance alone. regardless of a non-contributory family history.79 The observation of both ventricular dilatation and irregular density of white matter on brain imaging may suggest a neuronal migration defect. MIM 209880) Initially termed Ondine’s curse. (MEN 2A) and type 2B (MEN 2B). subjects with MEN 2B present with oral neuromas.58 59 Pigment related syndromes that may include HSCR include: (1) Yemenite deaf-blind hypopigmentation syndrome (MIM 601706). and congenital deafness (MIM 235740)82. life threatening condition characterised by abnormal ventilatory response to hypoxia and hypercapnia owing to failure of autonomic respiratory control. neural crest derived tumours (neuroblastoma. and FMTC. marfanoid habitus. a genetically heterogeneous condition. The MEN 2 syndromes include three types of cancer predisposition with an autosomal dominant mode of inheritance: familial medullary thyroid carcinoma (FMTC). RileyDay syndrome. Indeed. C609W. MEN 2B. contrary to what is observed in isolated HSCR.51 WS is clinically and genetically heterogeneous (MIM 193500. ataxia. Lyonnet Waardenburg syndrome illustrate each of these categories and can be associated with HSCR. and C620R RET gene mutations). probably autosomal recessive. is by far the most frequent condition combining pigmentary anomalies and sensorineural deafness (1/50 000 live births and 2-5% of all congenital deafness). resulting from the absence of melanocytes of the skin and the stria vascularis of the cochlea. homozygous mutations of the endothelin pathway53–56 and heterozygous SOX10 mutations have been identiﬁed in WS4 patients (see below).com . postaxial polydactyly. (2) Black locks-AlbinismDeafness Syndrome (BADS. Several reports with variable association of microcephaly.57 Patients carrying a SOX10 mutation may also present with CNS involvement including seizures.71 Mutations of the RET and the endothelin signalling pathways have been identiﬁed in rare CCHS patients: a RET mutation inherited from a healthy parent in two patients with Haddad syndrome.69 Recurrence risk in sibs is estimated as 5% with few multicase families reported. it is interesting to note that the FDS gene (IKBKAP) maps to 9q31 where a susceptibility locus for HSCR has been identiﬁed (see below). and hyperganglionosis of the hindgut. (4) HSCR and profound congenital deafness but with no other WS features has also been reported. (3) aganglionic megacolon associated with familial piebaldism (MIM 172800)62 63. MIM 223900) has been reported once in association with HSCR. ganglioneuroblastoma). multiple congenital anomalies-mental retardation syndrome combines HSCR. Multiple endocrine neoplasia type 2 (MEN 2).74 Other neurocristopathies Familial dysautonomia syndrome (FDS.
11q.4% in a series of 160 HSCR cases and may still be underestimated (personal data). persistent mullerian duct syndromes. HSCR has been reported in the HolmgrenConnor syndrome (MIM 211120).89 The MKKS disease causing gene on 20p12. So far. transient macrocytic anaemia. MIM 236700) and Bardet-Biedl syndrome (BBS.93 Smith-Lemli-Opitz syndrome (SLO.101 and (3) syndromes with central nervous system anomalies. genital.jmedgenet.108 Genital anomalies including hypospadias are reported in up to 2-3% of HSCR patients. and 16q.109–111 Finally. postaxial polydactyly. facial dysmorphic features. mostly atrio. endothelin 3 (EDN3). which may be allelic to CHH. and syndactyly between toes 2 and 3. (6) HSCR with brachydactyly.com . Isolated anomalies A wide spectrum of additional isolated anomalies have been described among HSCR cases with an incidence varying from 5% to 30% according to series. SLO results from cholesterol metabolic impairment with mutation of the 7-dehydrocholesterol reductase gene (DHCR7.99 100 (2) syndromes with dermatological ﬁndings. (7) BRESHEK syndrome. However. and genetics 733 235760)84.98 Interestingly. Skeletal x ray and cardiac and urogenital echographic survey should be systematically performed. renal involvement (including cysts. sparse. This is of interest since homozygous knockout mice for genes involved in the Ret signalling pathway present with renal agenesis/dysplasia in addition to megacolon (see below). 15q. facial dysmorphic features seem to be extremely frequent when looked for. eight genes are known to be involved in HSCR in humans. spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL. excluding patients with trisomy 21. chromosome 11q12-q13). TorielloCarey syndrome. Werner type. pyloric stenosis. or small bowel atresia are also found.88 and (8) mesomelic dysplasia. mutations in the MKKS gene were identiﬁed in some BBS patients conﬁrming clinical overlap at the molecular level. sensorineural. endothelin B receptor (EDNRB). has recently been identiﬁed. osteopetrosis. ﬁne. hypospadias. and SIP1 genes (table 4). whether an association with HSCR observed once is meaningful or occurred by chance alone is not possible to decide. These data highlight the importance of a careful assessment by a clinician trained in dysmorphology for all newborns diagnosed with HSCR. Aarskog syndrome. and blond hair.Hirschsprung disease. neurturin (NTN). heart defect. McKusick-KauVman syndrome (MKKS.or ventriculoseptal defects. MISCELLANEOUS OBSERVATIONS table 3 and can be classiﬁed as follows: (1) syndromes with muscular dystrophy.8 9 11 104–107 No constant pattern is observed and these anomalies include distal limb. mapped to chromosome arms 2q.97 The gene (RMRP) has been mapped to chromosome 9p13.91 92 Recently. single umbilical artery. Jeune asphyxiating thoracic dystrophy. These conditions are summarised in www. the eVect of genes playing a major role as compared to environmental factors (relative risk of 200). HSCR is associated with it in approximately 10% of the cases. Gastrointestinal malformations such as Meckel diverticulum. The observation of one additional anomaly to HSCR should prompt chromosomal studies.5 14 Consequently. (4) HSCR with preaxial polydactyly. Goldenhar syndrome.102 103 Other rare associations include the ﬁnding of HSCR with Fryns syndrome. central nervous system. and vertebral anomalies87. obesity. and asplenia with cardiovascular anomaly. skin. namely the protooncogene RET (RET). are found with an incidence of 5% of cases of HSCR. cardiac defects. HSCR is found in 10% of cases. or reduced ability to concentrate urine). BBS is genetically heterogeneous with at least ﬁve loci involved. macrocephaly. Renal dysplasia or agenesis was found in 4. HSCR has been reported in several BBS cases.170 OCCASIONAL ASSOCIATION IN RECOGNISABLE SYNDROMES The occasional association of HSCR with three syndromes or groups of syndromes of autosomal recessive mode of inheritance may be of interest for the identiﬁcation of susceptibility genes in HSCR. frontonasal dysplasia. combines metaphyseal dysplasia with short limb dwarﬁsm. glial cell line derived neurotrophic factor (GDNF). Rubinstein-Taybi syndrome.96 Cartilage-hair hypoplasia syndrome (CHH. endothelin converting enzyme 1 (ECE1). renal cortical loss. (5) HSCR with brachydactyly type D (MIM 306980)86. inguinal hernia. kidney.and postnatal growth retardation and microcephaly. severe mental retardation. SOX10. 3p. MIM 271640). and postaxial polydactyly of the hands and feet. HSCR has been assumed to be a sex modiﬁed multifactorial disorder. and congenital heart defect. and laryngeal anomalies (MIM 604211)85. Lesch-Nyhan syndrome.94 95 HSCR is observed in a signiﬁcant number of severe SLO patients. For rare disorders. associated syndromes. MIM 270400) SLO is characterised by pre.90 BBS is characterised by progressive pigmentary retinopathy. and immunodeﬁciency. encoding a chaperonin protein. and cardiac malformations. Molecular genetics Segregation studies in non-syndromic HSCR have shown that the recurrence risk in sibs varies from 1% to 33% depending on the gender and the length of the aganglionic segment in the proband and the gender of the sib (table 1). mild mental retardation. hypogenitalism. MIM 209900) MKKS is a rare condition characterised by hydrometrocolpos. MIM 250250) This skeletal dysplasia. ﬁrst described in the Old Order Amish community. Pallister-Hall syndrome.
a RET mutation is identiﬁed in only 50% of familial and 15-20% of sporadic HSCR cases. 143 144 57.2 in patients with TCA and mental retardation. GDNF mutations have been identiﬁed in only six HSCR patients to date. MR. where mutations occur in a cluster of six cysteines (exon 10.125 while haploinsuYciency is the most likely mechanism for HSCR mutations.com . 41 Mouse Natural mutant — — — Dom (AD) s (AR) ls (AR) — — l Amiel. GDNF needs the presence of a novel glycosylphosphatidylinositol (GPI) linked coreceptor GFRA1.2 5p13 19p13 22q13 13q22 20q13 1p36 2q22 Mode of inheritance AD AD AD AD AR/AD AR/AD AD Spo Phenotype in mutants HSCR HSCR HSCR WS4 WS4/HSCR WS4/HSCR HSCR CF and cardiac defect HSCR. such as RET mutations or trisomy 21.634). To activate RET.144 Finally. THE RET SIGNALLING PATHWAY The ﬁrst susceptibility locus was mapped to 10q11. abolished biological activity).129 Recent studies of known polymorphisms within the RET gene in a series of sporadic HSCR patients showed a signiﬁcantly diVerent distribution as compared to controls.2. failure to transport the protein to the cell surface.2 in multigenerational families segregating HSCR as an incompletely penetrant autosomal dominant trait. was regarded as a good candidate gene owing to the concurrence of MEN 2A and HSCR in some families and the expression in neural crest derived cells. identiﬁed as disease causing in MEN 2114 115 and mapping in 10q11. although Gfra1 homozygous knockout mice are phenotypically very similar to Ret and Gdnf -/. Spo: sporadic.118 Expression and penetrance of a RET mutation is variable and sex dependent within HSCR families.31 142 143 Moreover. 59. GFRA1-4. ls: lethal spotting. and can be regarded as a rare cause of HSCR (<5%). and an intracellular tyrosine kinase domain. no GFRA1 mutations have been identiﬁed in HSCR patients. was shown to be the RET ligand by both phenotypic similarities between Ret -/. nonsense. a simple activating versus inactivating model of gene action is not sufﬁcient to explain the concurrence of HSCR and MEN 2A in patients with a MEN 2A RET gene mutation. NTN.140 and artemin. a NTN mutation has been identiﬁed in one family.135 GDNF is a TGF-B related 211 residue protein.116 117 RET is a 1114 amino acid transmembrane receptor with a cadherin-like extracellular domain. In large series. 620. Consequently. most families with few exceptions are compatible with linkage at the RET locus. 39.122–124 In vitro. EDNRB and EDNRA are G protein coupled heptahelical proteins that transduce signals through the endothelins (EDN1. 142. sl: Piebald lethal. proteolytically cleaved to a 134 residue mature protein that homodimerises.136 137 Four related GPI linked coreceptors.mice. 611. MR: mental retardation.130 131 Epigenetic factors could also be involved. MEN 2 mutations have been shown to be activating mutations leading to constitutive dimerisation of the receptor and to transformation. in conjunction with a RET mutation. facial dysmorphism Frequence of mutation in heterozygotes 50% familial cases 15% sporadic cases 5 cases 1 case 5% <5% 1 case 6 cases Refs 119 31. S: short segment megacolon.44 114 115 and MEN 2B where the mutation is almost unique (M918T. GDNF. Despite extensive mutation screening. exon 16. namely GDNF. a cysteine rich region. 2.and Gdnf -/. CF: craniofacial. 157–160 156 162 38.145–148 THE ENDOTHELIN SIGNALLING PATHWAY The endothelin pathway was ﬁrst studied for its vasoconstrictive eVect and putative role in hypertension.119 Over 80 mutations have been identiﬁed including large deletions encompassing the RET gene. the estimated penetrance is 72% in males and 51% in females. L: long segment megacolon.734 Table 4 Genes involved in HSCR in humans and known mouse models of megacolon Human Gene RET GDNF NTN SOX10 EDNRB EDN3 ECE1 SIP1 Map location 10q11.139 persephin (PSPN). missense and splicing mutations. 3). residues 609. exon 11.138 and four related soluble growth factors ligands of RET have been identiﬁed.126–128 Biochemical studies showed variable consequences of some HSCR mutations (misfolding.112 113 This region had been targeted because of the observation of an interstitial deletion of chromosome 10q11.127 128 However. microdeletions and insertions. Several polymorphic haplotypes could be associated with predisposition to HSCR.33 The proto-oncogene RET. tyrosine kinase domain). GDNF mutations may not be suYcient to lead to HSCR since four out of six patients have additional contributory factors.jmedgenet. AR: autosomal recessive.141 Speciﬁc combinations of these proteins are necessary for development and maintenance of both central and peripheral neurones and all can signal through RET. Lyonnet Knock-out L Renal agenesis L Renal agenesis — L Coat spotting S Coat spotting S Coat spotting S Coat spotting CF defects — Refs 108 132–134 164 154 155 161 — AD: autosomal dominant. 618.31 142 Similarly.knockout mice132–134 and Xenopus embryo bioassays. known as a major survival factor for many types of neurones. residues 630. 165 53. RET gene mutations were identiﬁed in HSCR patients.149 150 www.119 However.119–121 There is no mutational hot spot at variance with MEN 2A.
165 Therefore. ECE1. and that S-HSCR is largely predominant. Others disrupt the transactivation domain and may result in a dominant negative eVect. the similarity of phenotype of the Ednrb knockout mice to that of the Edn3 knockout mice suggests that EDNRB’s major ligand is EDN3 in neural crest derived cells.167 Similarly.jmedgenet.com . www. Sox10 is involved in cell lineage determination and is capable of transactivating MITF synergistically with PAX3. According to the segregation analysis where an autosomal dominant model in L-HSCR and a multifactorial model in S-HSCR were more likely. the reduced expression of Ednrb in the dom mouse could arise either from a direct eVect of Sox10 or from an indirect eVect on a subset of NC cells of common faith. Ece1 processes only Edn1 and Edn3. SIP1). and genetics 735 A susceptibility locus for HSCR in 13q22 was suggested for three main reasons: (1) a signiﬁcant lod score at 13q22 in a large inbred Old Order Mennonite community with multiple cases of HSCR.163 The Dom gene is Sox10.55 56 Both EDNRB and EDN3 were screened in large series of isolated HSCR patients. and 13q22 in humans.36 37 153 and (3) synteny between the murine locus for piebald-lethal (sl). the W276C mutation was neither necessary (aVected wild type homozygotes) nor suYcient (unaVected mutant homozygotes) to cause HSCR. Moreover. RET + NTN. Taken all together. The critical role of the endothelin pathway in HSCR was shown by the ﬁnding that piebaldlethal was allelic to the Ednrb knockout mouse and harboured an Ednrb mutation (table 4). the observation of non-random association between HSCR.57 59 165 At least some mutations disrupt the DNA binding domain and may lead to a loss of function allele. HSCR is genetically heterogeneous and results from mutations in distinct pathways. RET plays a key role in non-syndromic HSCR genesis and multiple genes may be required to modulate clinical expression. homozygous Dom mutation being embryonic lethal. high mobility group (HMG) DNA binding proteins. several general comments can be made.30 151 152 (2) de novo interstitial deletion of 13q22 in several patients with HSCR. and penetrance was sex dependent (greater in males than in females).168 Therefore. Ece1 knockout mice show craniofacial defects and cardiac abnormalities in addition to colonic aganglionosis. associated syndromes.166 Each mutation was inherited from a healthy parent. SOX10 is unlikely to be a major gene in isolated HSCR. genetic heterogeneity.161 A heterozygous ECE1 mutation has been identiﬁed in a patient combining HSCR and craniofacial and cardiac defects (R742C). While EDN3 mutations were seldom found. These latest mutations were identiﬁed in patients presenting neurological impairment in addition to HSCR and pigmentary anomalies. INTERACTION BETWEEN PATHWAYS Ret and Ednrb signalling pathways were considered biochemically independent. heterozygous SOX10 mutations have been identiﬁed in familial and Multigenic inheritance of Hirschsprung disease As mentioned above. However.157–160 It is worth mentioning that the penetrance of EDN3 and EDNRB heterozygous mutations is incomplete in those HSCR patients. RET is the major gene in HSCR with a heterozygous mutation found in 50% of familial cases and 15-20% of isolated cases. Genotype-phenotype correlation is poor.30 151 This prompted a screen of the EDNRB gene in WS4 and homozygous mutations in a fraction of WS4 families were found. Preproendothelins are proteolytically cleaved by two related membrane bound metalloproteases to give rise to the mature 21 residue endothelin. EDN3.154 Subsequently. two approaches have been chosen to test these hypotheses in L-HSCR and S-HSCR independently. Ednrb transcripts are either absent or drastically reduced in Dom -/.and +/. although sibs sharing a mutation and discordant for HSCR have been described in one family. an Edn3 mutation was identiﬁed in the lethal spotting (ls) natural mouse model for WS4155 and EDN3 homozygous mutations were identiﬁed in WS4 in humans (table 4). a member of the SRY (sex determining factor)-like. and chromosome 21q22 in the Menonnite population where HSCR imperfectly segregates with an EDNRB mutation favours multigenic inheritance resulting from the cumulative eVects of multiple mutations. RET.162 SOX10 isolated patients with WS4 (including de novo mutation). Interstitial 13q22 deletions encompassing the EDNRB gene in HSCR patients make haploinsuYciency the most likely mechanism for HSCR (table 2). The last de novo mouse model for WS4 in human is dominant megalon (Dom). de novo mutations have not hitherto been observed.Hirschsprung disease.59 Penetrance appears to be high. an HSCR patient heterozygous for weak hypomorphic mutations in both RET and EDNRB has recently been reported. respectively. so that again haploinsuYciency is the most likely mechanism for HSCR. G protein coupled receptors and receptor tyrosine kinases could be engaged in crosstalk.53 However. EDNRB.164 Subsequently. has been reported (RET. Some patients with mutations in more than one HSCR susceptibility gene are known (RET + GDNF. However. RET + EDNRB). a model of aganglionosis.53 piebald-lethal was considered a mouse model for WS4 in humans and some of the aVected Mennonite subjects had pigmentary anomalies and sensorineural deafness in addition to HSCR. On the other hand. RET mutation penetrance is incomplete and sex dependent.156 EDNRB mutations were identiﬁed in approximately 5% of the patients.mice. Although EDNRB binds all three endothelins. an EDNRB missense mutation was identiﬁed in the Mennonite kindred (W276C).54 At the same time. where mutation in one of several genes is suYcient for phenotypic expression of HSCR.
31 Salomon R. Carter C. Lyonnet LINKAGE ANALYSIS IN 12 HSCR FAMILIES WITH THREE OR MORE AFFECTED SUBJECTS IN TWO OR MORE GENERATIONS 129 L-HSCR is largely predominant in these families.3:1217-25.26:261. 4 Swenson O. Gimelli G. J Pediatr Surg 1996. 26 Moore SW. Lutterbeck PM. Hum Mol Genet 1994.53:1023-7. Anguita FA. Evian. Pachnis V. Ultrashort Hirschsprung’s disease: myth or reality.9:321. Hirschsprung’s disease . Ricour C. Morger R. The metabolic and molecular bases of inherited diseases.7:11-17. Hirschsprung’s disease. 3 Meier-Ruge W. Many HSCR cases are associated with other congenital anomalies. Ribas J.31:1003-8. Wakizaka A. 16 Nihoul-Fékété C. Bratton B. Genetic counselling HSCR is a sex modiﬁed.7:308. et al.27:1. 21 Kurer MH. 25 Yanchar NL.61:83-4. J Pediatr Surg 1998. Therefore. Linkage to a novel locus in 9q31 was identiﬁed only in families with no or hypomorphic RET gene mutation. a severe RET mutation may lead to phenotypic expression by haploinsuYciency. Apropos of 76 cases. Jb Kinderheilkd 1888. Myenteric plexuses in congenital megacolon. Attie T. Bidaud C. Nihoul-Fekete C. J Pediatr Surg 1996. Meijers C. www. J Pediatr Surg 1972. Tohoku J Exp Med 1999. Loygue J. Filler RM. Soylet Y. Nirasawa Y. 33 Martucciello G. J Pediatr Surg 1990.jmedgenet. Matise TC. a unifying concept of disease arising in neural crest maldevelopment. France. Total colonic aganglionosis. Hirschsprung disease in a large birth cohort. The neural crest. a splice mutation in two families. Munnich A. Breuning MH.28:503-8. Dodero P. 12 Brooks AS. unfortunately. Ladda R. Goulet O. Weissenbach J. In isolated HSCR. Clinical outcome and long-term quality of life after surgical correction of Hirschsprung’s disease. Identity-bydescent and association mapping of a recessive gene for Hirschsprung disease on human chromosome 13q22. EYciency of the anorectal manometry for the diagnosis of Hirschsprung’s disease in the newborn period. KauVman ER. congenital malformation with an overall recurrence risk in sibs of the proband of 4% (relative risk=200). which could explain the sex diVerence in HSCR expression. 28 Jasonni V.13:479-85. Teratology 1985. 22 Soave F.7:174-80. Because of poor genotype-phenotype correlation so far. Sarimurat N. Technique and results of Soave’s operation.34:158-62. Gomez de Terreros I.736 Amiel. Acetylcholinesterase activity in suction biopsies of the rectum in the diagnosis of Hirschsprung’s disease.47:61-8. Semin Pediatr Surg 1998. We sincerely acknowledge colleagues from all over the world for providing us with samples as well as all the students and collaborators of our research group on Hirschsprung disease. 8 Passarge E. Cambridge: Cambridge University Press. Pellerin D. Kilic N. Martelli H. A SIB PAIR ANALYSIS IN 49 FAMILIES WITH S-HSCR PROBANDS 169 This study shows that only three loci on chromosomes 3p21. 14 Badner JA. Suction biopsy in Hirschsprung’s disease.276:138-43. Erdogan E. 20 Lopez-Alonso M. 11 Spouge D.32:171-7. ed. Spitz L.33:830-3. Chakravarti A. Germline mutations of the RET ligand GDNF are not suYcient to cause Hirschsprung disease. Yazbeck S. Hum Pathol 1973. 19 Emir H. Martinez-Caro A. Angrist M. Several known syndromes have straight Mendelian inheritance. Total colonic aganglionosis (with or without ileal involvement): a review of 27 cases. A family study of Hirschsprung disease. 30 PuVenberger EG. Moser R. Smith B. Baird PA. Biocchini M.5:160-3. Some data in the present review have been reprinted and adapted from Scriver CR. Arch Dis Child 1986. Slaugenhaupt SA. Long-term outcome after Hirschsprung’s disease: patients’ perspectives. Br J Surg 1966. Ito Y. Clin Genet 1985. 1 Hirschsprung H. Curr Opin Genet Dev 1999. An epidemiological study of Hirschsprung’s disease. J Pediatr Surg 1986. 10q11. Am J Hum Genet 1990. 27 Albanese CT.the Duhamel modiﬁcation. Law JC. Scharli A. 9 Goldberg EL. Lyonnet S. Nat Genet 1996.14:345-7. Eur J Pediatr Surg 1995. Evidence for heterogeneous etiology and a study of sixty-three families. Interestingly.21: 251. Early history of the therapy of Hirschsprung’s disease: facts and personal observations over 50 years. Kiely EM.31:1496-502. Martucciello G. Ricour C. is not yet routine practice. This. N Engl J Med 1967. Garver B.82: 75. 15 Taraviras S. multifactorial. Akman M.20:133-41. A genetic study of Hirschsprung disease. Hernandez A. Pediatr Surg Int 1992. This emphasises the importance of careful assessment by a clinician trained in syndromology of all newborns diagnosed with HSCR. 18 Parc R. 24 Hackam DJ. Eur J Pediatr Surg 1999. Stuhlträgheit neugeborener infolge von dilatation und hypertrophic des colons. Herzog B. 1999. The Third International Meeting: Hirschsprung disease and related neurocristopathies. Pierro A. Enterocolitis after the surgical treatment of Hirschsprung’s disease: risk factors and ﬁnancial impact. Development of the mammalian enteric nervous system. 2 Whitehouse F. Perineal one-stage pull-through for Hirschsprung’s disease. Washington SS. 5 Bodian M. 8th ed. Bolk S. and 19q12 are both necessary and suYcient to explain the incidence and sib recurrence risk in HSCR. Megacolon in adults.187:43-7. The genetics of Hirschsprung’s disease. Sarnacki S. Spectrum of phenotypes associated with Hirschsprung disease: an evaluation of 239 patients from a single institution. marker analysis showed a signiﬁcant parent of origin eVect at the RET locus. Point nucleotidic changes in both the RET proto-oncogene and the endothelin-B receptor gene in a Hirschsprung disease patient associated with Down syndrome. Management and long-term follow-up of infants with total colonic aganglionosis. adequate relative risk ﬁgures will be provided by taking into account the sex and length of the aganglionic segment in the proband and the gender of the sib (1-33%). and no coding sequence variation in three families.46:568-80. Albertyn R. According to the Carter paradox. Jennings RW. J Pediatr Surg 1999. Lortat Jacob S. Ann Hum Genet 1963. Amiel J. Cywes S. the beneﬁt of mutation screening for HSCR patients appears low except for systematic testing of exon 10 and 11 of the RET gene owing to cancer predisposition of MEN 2A mutations. Mascari M. Berrod JL. Mutational analysis identiﬁed a nonsense or missense mutation at a highly conserved residue in six families. Tussiot J. 32 Sakai T. Puliti A. Pearl RH.5:409-29. J Pediatr Surg 1999. 6 Bolande RP. All but one family showed linkage to the RET locus. Sieber WK.25:1135-8. An epidemiological study of Hirschsprung disease in a multiracial California population. while hypomorphic RET mutations would require the action of other mutations. Eng C. New York: McGraw-Hill:6231-55. Chap 251. 7 Le Douarin N. 78% of shared RET alleles being maternally derived. Kernohan J. Pelet A. The neurocristopathies. Anorectal manometry during the neonatal period: its speciﬁcity in the diagnosis of Hirschsprung’s disease. Harrison MR. Kalcheim C. A multiplicative risk across loci with most affected subjects being heterozygotes at all three loci seems the best genetic model. 1998. 23 Newbern WR. 29 Tsuji H. Finally. Pambakian H. study of 11 cases. We thank the HSCR patients and their families and the French Hirschsprung Disease Association (AFMA) for their cooperation and active participation over 10 years. 1998. France. Total colonic aganglionosis associated with interstitial deletion of the long arm of chromosome 10. Drake DP.34:1152-60. In these cases.com .34:377-80. Ann Gastroenterol Hepatol (Paris) 1984. Soucy P. Evian. 17 Neilson IR. Hirschsprung disease: a genetic study. Chakravarti A. Lawson JO. the highest recurrence risk is for a male sib of a female proband with L-HSCR (table 1). J Pediatr Surg 1999. Cirillo M. Garver KL. Arch Intern Med 1948. 13 Torfs CP. Int J Epidemiol 1984. The Third International Meeting: Hirschsprung disease and related neurocristopathies. Am J Gastroenterol 1967. linkage to 9q31 was conﬁrmed in the sib pairs with no or hypomorphic RET mutation. the long term prognosis is highly dependent on the severity of the associated anomalies.9:101-3. 10 Garver KL. Garver KL.
Obladen M. Point mutation in exon 12 of the receptor tyrosine kinase protooncogene RET in Ondine-Hirschsprung syndrome. Solish SB. Schinzel A. 65 Gozal D. SOX10 mutations in patients with WaardenburgHirschsprung disease. Meijers C. Fitchett M. Fitchett M. Attie T. An unusual demyelinating neuropathy in a patient with Waardenburg’s syndrome. Shprintzen RJ. Weeks FF.83:670-4.8:161-3. Betsos N. Pelet A. and neuroblastoma manifestations of neurocristopathy. 83 Laurence KM. Cys 618 Arg mutation in the RET proto-oncogene associated with familial medullary thyroid carcinoma and maternally transmitted Hirschsprung’s disease suggesting a role for imprinting. 62 Mahakrishnan A. Pediatrics 1985. Nat Genet 1996. Separation of retinoblastoma and esterase D loci in a patient with sporadic retinoblastoma and del(13)(q14. Arch Fr Pediatr 1989. Yakobson E. Heterogeneity in Waardenburg syndrome. Brochu P. Wegner M. Am J Hum Genet 1996. Kamsteeg EJ. Report of a kindred with multiple disorders. 52 Hageman MJD. Attie T.25:204-5. Heinrichs C. Manceau E. Goossens M. Osinga J.62:715-17. 60 Bondurand N. Matthijs G. Pelet A. gastrointestinal motility and heart rate. and ulnar polydactyly in sibs: a case for fetoscopy. Munnich A. 77 Merkler RG. 51 Waardenburg PJ. 49 Romeo G. Am J Hum Genet 2000. Hennekam RC.101:924-6. Sane SM. Pediatr Pulmonol 1998. Lyonnet S. Pingault V. Wu Y. Enderich J. 50 Borrego S. Oh KS.79:1257-66. 74 Bolk S. 47 Peretz H. Eng C. Leal MJ.7:129-34. 76 Michna BA.3:195-253. Chakravarti A. Kerr BA. Familial neuroblastoma. Wilson J. Doerﬂer W. Lacombe D. Boutrand L. Endothelin-3 frameshift mutation in congenital central hypoventilation syndrome. Croaker GD. Yanagisawa M. Familial association. Martucciello G.47:360-7. Seri M. Safar A. Mutational analysis of multiple endocrine neoplasia type 2A associated with Hirschsprung’s disease. Itoh Y. Mulligan LM. 46 Caron P. Kumar D. Edery P. Luboshitsky R. 72 Amiel J. Legius E. Voorhess ML. Amiel J. Adam E. Gershoni R. Hum Mol Genet 1994. hypertelorism. Coexistent neuroblastoma and Hirschsprung’s disease -another manifestation of the neurocristopathy? Pediatr Radiol 1979. Antinolo G. Am J Med Genet 1998.jmedgenet. Mellins RB. Attie-Bitach T. microcephaly. Nomura N. Lyonnet S. Sonta S.Hirschsprung disease. Pingault V. Srinivasan MS. Wegner M. Medicine 1978. Eng C.27:369-70. Yanagisawa M. Am J Med Genet 1988. Xie YG. Hum Genet 1991. Congenital central hypoventilation syndrome: an update. Molecular analysis of the ret and GDNF genes in a family with multiple endocrine neoplasia type 2A and Hirschsprung disease. 55 Hofstra RM. Congenital central hypoventilation syndrome: inheritance and relation to sudden infant death syndrome. Piebaldness with Hirschsprung’s disease. Mutations of the RETGDNF signaling pathway in Ondine’s curse. Currarino G. 63 Kaplan P. 67 Roshkow JE. Kuhlbrodt K. Wulfsberg EA. Buys CH. Driscoll JM. Mushiake K. Cass DT. Bidaud C. A new syndrome combining developmental anomalies of the eyelids. 81 Halal F.66: 1496-503. 70 Haddad GG. Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotype-phenotype correlation. Multiple endocrine neoplasia type 2 and RET: from neoplasia to neurogenesis. David D. Hirschsprung’s agangliosis and jaw-winking syndrome. Magenis RE. McWilliams NB. Herbarth B. and mental retardation.5:11-14. Celli J. Association of multiple endocrine neoplasia type 2 and Hirschsprung disease. de Chaderevian JP. cell migration disorder of the neurocytes of the gut. Xie J. 69 Weese-Mayer DE. Binkert F. Tan-Sindhunata G. Auge J. A molecular analysis of the Yemenite deaf-blind hypopigmentation syndrome: SOX10 dysfunction causes diVerent neurocristopathies. Pelet A. Hum Genet 1984. Besserman AM.31:679-88. Vekemans M. Chakravarti A. mental retardation. Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene. Washington SS. Dennis NR. Mulligan LM. Familial occurrence of neuroblastoma. Aigrain Y. Smith JC. Vitoux C. Hofstra RM. Autosomal-recessive neural crest syndrome with albinism. Eng C.1q22. 53 PuVenberger EG. Peacock ML. Nat Genet 1996. 78 Clausen N. Unknown syndrome: Hirschsprung’s disease. Ceccherini I. and deafness: ABCD syndrome. Buckmaster DA. Demarquez JL. including neuroblastomas in four siblings. Jacky PB. Puliti A. Andersson P. microcephaly. Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome). Am J Hum Genet 1977. Huson SM. Encha-Razavi F. Taniguchi H. J Clin Endocrinol Metab 1996. Lamb OA. and congenital deafness: a new autosomal recessive syndrome. Nakao K. Munnich A. 79 Goldberg RB.19: 45-9. Tam PK. RebuVat E. Read AP. Hirschsprung megacolon and cleft palate in two sibs. Am J Med Genet 1995. cause a form of Hirschsprung disease. Scherzer AL. Usher S.12:445-7. unilateral renal agenesis. Gaultier C. Weber AM.46:595-7. Genet Couns 1994. 82 Santos H.13:395-6. Warburg M. Munnich A. encoding Smad interacting protein-1. Navarro J. Kunze J. Marazita ML. 58 Jacobs JM. 64 Weinberg AG. Verellen-Dumoulin C. Boige N. Amiel J. Lyonnet S. GraV E. Blanc WA. Frilling A. Hosoda K. Phenotypic variability of del(2) (q22-q23): report of a case with a review of the literature. Silvestri JM. Tommerup N. Lerone M. Angrist M. J Med Genet 1998.3q33. Hum Mol Genet 1999. Salk DJ. J Med Genet 1989. 38 Lurie IW.56:322-6. Acta Paediatr Scand 1989. deWit D.29:468-85. J Pediatr Surg 1988. Berry TL. Munnich A.2q21. Interstitial deletion of distal 13q associated with Hirschsprung’s disease. 35 Sparkes RS. Prosser R. Kitoh H. Morel J. J Pediatr Gastroenterol Nutr 1982. Hyland VJ. Amiel J. Black MH. Meningomyelocele and Hirschprung disease: theoretical and clinical signiﬁcance.152:75-7. Hirschsprung’s disease. 117:386-91. NivelonChevallier A.26:273-82. Grynberg E.87:748-50. Peacock ML. Multifocal ganglioneuroblastoma coexistent with total colonic aganglionosis. Currie J. Nat Genet 2001. 42 Hansford JR. Hirschsprung’s disease in a family with multiple endocrine neoplasia type 2. Congenital failure of automatic control of ventilation. Yin L. Lyonnet S. Venter DJ.2): potential mapping of one disease locus. J Clin Endocrinol Metab 1998. Hartenberg MA. Cadotte M. Martelli H. J Med Genet 1988. Hum Mutat 1997. Nirasawa Y. Brown MG. Lawce HJ. van Ravenswaaij-Arts C. Matsuda H.68:258-9. 75 Gaisie G. Wakizaka A. Hum Mol Genet 1998. Durum CT.1:603-7. Olson CL. Nagaya M. On T. Cell 1994. Goossens M. 36 Lamont MA. N Engl J Med 1967. Mazza NM. Sanchez B. J Med Genet 1988. Yamada Y. Neurocristopathy. Am J Hum Genet 1951. unusual face.25:494-7. The syndrome of Hirschsprung disease. Hirschsprung disease. 41 Wakamatsu N. Brett EM. Clinical outcomes of four patients with microdeletion in the long arm of chromosome 2. Priolo M. Weese-Mayer DE. Attie T. The association of Hirschsprung’s disease-ganglioneuroma with autonomic nervous system dysfunction in 2 children.1:185-9. Goerich DE.78:736-41.18:171-3. Rosenblum-Vos LS. Romeo G. Trang H. 66 Chatten J. Munnes M. Lyonnet S. A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome). Epstein RA.37:106-8. Chaitow J. associated syndromes. Yamada K. del(13)(q32. Prehu MO. Defendini R. A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung’s disease. 71 Verloes A. 43 Verdy M. Haller JO. Nat Genet 1998. Moncla A. Mutations in SIP1.81:2731-3. 57 Pingault V.78:36-43. Young LW. Holschneider AM. Chakravarti A. Further delineation in two cases and review of the literature. Hermans-Borgmeyer I. 56 Edery P. Baron E. Stulp RP. Markiewicz M. Majoor-Krakauer D. Surgery 1995. Gunter KA. Wilson MJ. Salzberg AM. Saez ME. Mutoh N. C618R mutation in exon 10 of the RET proto-oncogene in a kindred with multiple endocrine neoplasia type 2A and Hirschsprung’s disease. 73 Sakai T. 54 Attie T. Lyonnet S. Berdon WE. von Recklinghausen’s neuroﬁbromatosis. Watson P. J Intern Med 1998. Disteche CM. Bondurand N. J Med Genet 2000.2): a further link with the neurocristopathies? J Med Genet 1994. Arch Dermatol 1980. Reiss JA. Bonardi G. Attie T.3). Am J Med Genet 1990. Pearson JF. Hoo JJ. Richard C. Kuhlbrodt K. Amiel J. 31:325-7. 23:57-9. Piebaldism-Waardenburg syndrome: histopathologic evidence for a neural crest syndrome. Thomson AH. Roy CC. Hirschsprung’s disease associated with congenital heart malformation. broad big toes. Grimmer I. Yoshitomi MJ. 45 Borst MJ.76:299-300. Kato K. Robinson BG. Jasonni V. Ceccherini I.57:517-26. J Craniofac Genet Dev Biol 1981. 48 Decker RA. Ondine’s curse. 39 Mowat DR. Sparkes MC. Elmer C. J Med Genet 1975. Chia NL. Ondine-Hirschsprung syndrome (Haddad syndrome). 44 Mulligan LM. Boureau M. Rocker I. Hirschsprung’s disease associated with a deletion of chromosome 10 (q11. Sarda P.12:334-8. 12:442-4.4:2407-9. Nat Genet 1996. Maier RF. Roger P. Navarro E.3:2163-7. Morin CL. Pelet A. Brousset F. Mateus J. Stoltenburg-Didinger G. 80 Hurst JA. Kalina RE. Salomon R. 37 Bottani A.37:817-27.243:515-20.35: 617-23. 61 Gross A.116:1102. Biton A. microcephaly. Hum Genet 1977. Mutation of the endothelinreceptor B gene in Waardenburg-Hirschsprung disease. Lapidot M. Angrist M. Yamanaka T. eyebrows and nose root with pigmentary defects of the iris and head hair and with congenital deafness.38:157-61. Munnich A. black lock.8:1785-9.26:100-4. Pediatrics 1998. Till M. Korsch E.83: 3361-4. Am J Med Genet 1993. Tommerup N.277:1230-6. Lyonnet S. Munnich A. 68 Levard G. 40 McMilin KD. Read AP. Supovitz KR. Acta Neuropathol (Berl) 1992. Marsh DJ. Hirschsprung’s disease and congenital deafness. A case of Hirschsprung disease with a chromosome 13 microdeletion. Epstein MA. Ades LC.10:155-9. Krummel TM. Pagon RA.com . Silvestri JM. Goossens M. Hirschsprung disease associated with polydactyly. Hum Mol Genet 1995. and genetics 737 34 Fewtrell MS. Ponder BAJ. Sajus M. Eur J Pediatr 1993. and characteristic facial features: delineation of a new syndrome and identiﬁcation of a locus at chromosome 2q22-q23. 59 Touraine RL. Olson SB. Pediatr Radiol 1988. and iris coloboma: a new syndrome of defective neuronal migration. Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain. Decker RA. Mokhtari M. www. VanCamp JM.
Point mutations aVecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung’s disease. 115 Donis-Keller H. PollThe BT. Am J Hum Genet 1998. vertebral defects. A gene for Hirschsprung disease (megacolon) in the pericentromeric region of human chromosome 10.3:237-41. 92 Lorda-Sanchez I. Ceccherini I. Mok-Siu V. Lyonnet S. 105 Edward E. Kraus MH. Boutrand L. Miranda C. Lopez-Alonso M.63: 55-62. Matoskova B. Abel L. J Clin Invest 1998. and colonic aganglionosis in sibs. 107 Sarioglu A.367:375-6. Antinolo G. Vreken P. 125 Santoro M. 98 Sulisalo T. Eng C. Pasini B. Holder S. Mulligan LM. Brain anomalies. Sieber W. Stelwagen T. X linked recessive inheritance of agenesis of the corpus callosum.3: 686].51: 480-1. Hordinsky M. Romeo G. Berlingieri MT. SheYeld VC. Hicsonmez A. The KaufmanMcKusick syndrome: another association. 93 Slavotinek AM. A new syndrome: heart defect. Nature 1993.367:378-80. 130 Borrego S. Pasquino B.34:670-1. Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene. Genet Med 1999. Edery P. 127 Carlomagno F. Rest EB. Grieco M. Macrocephaly.367:377-8. Pasini B. Am J Med Genet 1993.90:80-1. Berry SA. Nagai MA. Eng C. Bolino A. Ecker J. Elias ER. Kravcenkiene I. Billaud M.36:771-4. Howe JR. Elsdon MJ. J Pediatr Surg 1992. Goodfellow P. Atti T. J Med Genet 1997. Parfrey PS. Seri M. Hirschsprung’s disease. Saez ME. Luo Y. Frequency of RET mutations in long. Hofstra RM.20:122-4. Seri M. Scavarda N. 129 Bolk S. Loss of function eVect of RET mutations causing Hirschsprung disease. De Vita G. 124 Carlson KM. Eng C. 112 Lyonnet S. Connor WE. Frick R. Braun J. J Med Genet 2000. Buyukpamukcu N.4:1381-6. Hirschsprung disease in a 46. Lenoir G. Hum Mol Genet 1994. Chakravarti A. 131 Borrego S. Nature 1994.and short-segment Hirschsprung disease. Pediatrics 1983. J Pediatr Surg 1997.47:37-40. Gorlin RJ. Green JS. Asch MJ. Hirschsprung’s disease: associated abnormalities and demography. KauVman E. and minor dysmorphic features: a distinct autosomal recessive syndrome? J Med Genet 1988. Nihoul-Fekete C. Radice MT. Stulp R. Pasini A. Brik R. van Amstel HKGR. Dou S. Takahashi M. Smeitink JA. Hum Mol Genet 1995. Mutation of a gene encoding a putative chaperonin causes McKusickKaufman syndrome. Ileal atresia with total colonic aganglionosis. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Kirse DJ. Moley JF. Pasini B. Ceccherini I. Martucciello G. J Pediatr Surg 1989. Proc Natl Acad Sci USA 2000. Colantuoni V. Devoto M. Eng C. Nat Genet 2000. Kaitila I. Love DR. Hall W. Melillo RM. 121 Seri M. Phillips H.25:79-82. 88 Reish O. Briard ML. Niebuhr E. Berant M. Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours [published erratum appears in Hum Mol Genet 1994. Gardner E. Lyonnet 84 Al-Gazali LI.27:76. Scheumann GF. Dow E. 123 Hofstra RM. Congenital muscular dystrophy with neurological abnormalities: association with Hirschsprung disease. Chandler JG. 91 Radetti G. J Pediatr 1983. Helv Paediatr Acta 1988.25:758-61. Martucciello G. Science 1995. Nature 1994. brachydactyly. Farinas I. 90 Stone DL. Silengo M.43:249-52. 96 Patterson K. 114 Mulligan LM. Z Kinderchir 1986. Ponder BA. Healey CS. Luo Y. al-Alaiyan S. Bongarzone I. Angrist M. eye hypoplasia. Dathan NA. Reichardt LF. 152:211-17. Mykytyn K. de la Chapelle A. Exon structure and ﬂanking intronic sequences of the human RET proto-oncogene. Familial Hirschsprung’s disease and type D brachydactyly: a report of four aVected males in two generations. Nat Genet 1993. Jackson CE. Munnich A. Nat Genet 1995. Wanders RJ. Duran M. 117 Romeo G. Pelet A.4:351-6. Chakravati A. Pelet A. Weissenbach J. Yin L. Romeo G. Germline mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.10:35-40. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. 103 Okamoto N. 128 Pelet A. aganglionosis. Toshima K. Biesecker LG. PuVenberger EG. Savage MO. Chi D. Acta Paediatr 1994. Reyna T. Coincident or common etiology? Am Surg 1985. Cass DT. 122 Eng C. Pelet A. Pierotti MA. Nature 1994. Wayne ER. Romano A. Goto S. Sauer H. A gene for Hirschsprung disease maps to the proximal long arm of chromosome 10. Hastbacka J. Nihoul-Fekete C. Lipson A. Washington SS. Additional anomalies in Hirschsprung’s disease: an analysis based on the nationwide survey in Japan. Komar K. Abramowicz MJ. Christakis N. Mutations in the human sterol delta7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome. An epidemiological study of Hirschsprung’s disease and additional anomalies. Musarella MA. Casasa JM. Hum Mol Genet 1995. Donis-Keller H. Mulligan LM. Toshima K. Vecchio G. Ponder BAJ. 113 Angrist M. Wevers RA. 99 Mandel H. Hirschsprung disease. Ryan AM. Tanyel FC. Abel L. 106 Russell MB. Ruiz A. Mulliken JB. Hofstra R. Wells SAJ. Munnich A. Cartilage-hair hypoplasia gene assigned to chromosome 9 by linkage analysis. Barone V. Higgins JV. Lopez-Alonso M. Price MR. KristoVersson U. J Med Genet 1999. Renal and neuronal abnormalities in mice lacking GDNF. Dorland L. 118 Ceccherini I. Linck LM.6:24-7. Dou S. Ponder MA. 102 Kaplan P. and other minor anomalies. Ruiz A. Lairmore TC. Situs inversus and Hirschsprung disease: two uncommon manifestations in Bardet-Biedl syndrome. RET genotypes comprising speciﬁc haplotypes of polymorphic variants predispose to isolated Hirschsprung disease. ear deformity and deafness. PuVenberger EG. Martucciello G. EMBO J 1996. Hydrocephalus and Hirschsprung’s disease in a patient with a mutation of L1CAM.9:275-7. Healey CS. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Luo Y. 100 Kim JJ. Beldjord C. Croaker D. Bolk S. Hum Mutat 1997. Report of two patients with hypertrophic pyloric stenosis and Hirschsprung’s disease. and short stature. Burke B. Lerone M. Pachnis V.382:76-9. Waterman DF. retardation of mentality and growth.2:851-6. Alford BA. Puliti A.103:425-7. Ludatscher R. Geneste O. Nihoul-Fekete C. Cartilage-hair hypoplasia .738 Amiel.24:1192-4. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Kraus MH. Various mechanisms cause RET-mediated signaling defects in Hirschsprung’s disease. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Buys CH. Kaitila I. Armstrong DD. Barber JC.68:386-90. Eur J Pediatr Surg 1997. Mengarda G. Rosenthal A. Chakravarti A. Kelly TE. Am J Med Genet 2000. Nat Genet 1993. Barr M. J Child Neurol 1994. Multicore myopathy. Bocciardi R. Hirschsprung-associated congenital anomalies. BouVard GG. Barone V. 108 Schuchardt A. Lyonnet S. 97 Makitie O. Bolino A. 101 Mallory SB. Ibanez A. Speciﬁc polymorphisms in the RET proto-oncogene are over-represented in patients with Hirschsprung disease and may represent loci modifying phenotypic expression. A human model for multigenic inheritance: phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locus. Ceccherini I. Mutations in MKKS cause BardetBiedl syndrome. 119 Attie T. 109 Whalen TV Jr.1:155-7. Barone V. Chandra RS.37:572-8.27: 204-6. Mole SE. Nature 1994. Jackson CE. Luo Y.26:15-16. Cass DT.267:381-3. Bottaro DP.63:329-38.196:1288-95. Vanderwinden JM. Pasini B. Carlomagno F. Ayuso C. Weeks DE. Borrello MG.1:104. Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease. Janik JS. Nat Genet 2000.97:268-73. Holmes LB. TunnacliVe A.4:821-30. Di Fiore PP. 126 Pasini B. Am J Hum Genet 1998. Molecular heterogeneity of RET loss of function in Hirschsprung’s disease. Bocciardi R. Kwok JB. Romeo G. Banerjee-Basu S. Heckenlively JR. ectodermal dysplasia. hypoplastic nails. Dickson JA. Santoro M. 104 Ikeda K. Toomey KE. Kaariainen H. Porter FD. Ichthyosis. Romeo G. Munnich A. Celli I. Fishman MA. Hum Mol Genet 1993.32: 1502-3. Matise TC. Slaugenhaupt SA. Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung disease.71:246-9. Maslen C. Mulligan LM. Luo Y. Baric I.83:68-71. Fusco A. Gardner E. Steiner RD. Larsson LT. Salomon R.101:1415-23. Smith DP. Makitie O. 111 Janik JP. skeletal malformations. Wright FA. Cass DT. Hoppener JW.jmedgenet. Armanini M. Dysmorphol Clin Genet 1988. Chappuis S. Hennekam RC. Lerone M. Edery P. Greco A. Wadelius C. Hirschsprung disease.7:331-7. Carver-Moore K. Goto M. Sistonen P. Ponder BAJ. Gao X. 116 Edery P. Agenesis of corpus callosum. Nature 1996. 87 Toriello HV. Mondellini P. Papi L. Eur J Pediatr 1993.363:458-60. Buys CH. Wijburg FA. Landsvater RM. Folkman J. Kachilele-Linjewile S. Russell CA. Klein RD. Gimm O. Alberti L. de Franciscis V. Lin D. Baxevanis AD. Heon E. and Hirschsprung’s disease. cryptorchidism. Williams ML. 120 Angrist M. Biochem Biophys Res Commun 1993. Thiel B. Slavotinek A.XY phenotypic infant girl with SmithLemli-Opitz syndrome. Saez ME.41:279-81.367:380-3.3:338-41. Wells SA. Fusco A. Munnich A. 86 Reynolds JF. 132 Moore MW. Amiel J. Bocciardi R. Lawrence C. Bocciardi R. preaxial polydactyly. Mutations of the RET proto-oncogene in Hirschsprung’s disease. Larsson-Blomberg L.com . www.91:1579-83. 94 Wassif CA. Kaariainen H. microcephaly. Stone EM. Arighi E.4:346-50. cleft palate.clinical manifestations in 108 Finnish patients. Lyonnet S. 89 Davenport M. Goodfellow PJ.9:243-9. Biesecker LG. J Med Genet 1983. Gimm O. Costantini F. Pediatr Dermatol 1989. Wada Y. Moore JK. hypertrophic pyloric stenosis and Hirschsprung disease: coincidence or common etiology? Neuropediatrics 1996. laryngeal anomalies. 85 Huang T. Mueller RF. Taitz LS. Antinolo G. Carlson KM. Lerone M. Proc Natl Acad Sci USA 1994. 95 Waterham HR. Haynie LS. and kidney dysplasia/ hypoplasia (BRESEK/BRESHECK): new X-linked syndrome? Am J Med Genet 1997. Hypothalamic-pituitary dysfunction and Hirschsprung’s disease in the Bardet-Biedl syndrome. 110 Sayed M. Hofstra RM. Chi D. Nat Genet 1993. deafness.15: 2717-25. Ronchetto P. Pelet A. Lyonnet S. Hernandez A. Jira PE. Donnai D. D’Agati V.
von Deimling A. Antonio L. Sariola H. Eng C. Neuron 1998. Amiel J. GDNF signalling through the Ret receptor tyrosine kinase. Westphal H. Chakravarti A. Attie T. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Hu Z. Am J Hum Genet 1999. Am J Hum Genet 1999. Bondurand N. Werner’s mesomelic dysplasia with ventricular septal defect and Hirschsprung’s disease. Costantini F. Bolk S. Endothelin-3 gene mutations in isolated and syndromic Hirschsprung disease. Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene. Baloh RH. Hum Genet 2000. Agarwala R.64:304-8.86:2863-7. Wartiowaara K. Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient. SteVann J. Hammer RE. Giaid A. Tansey MG.com . Sariola H. 156 Bidaud C. Mulligan LM. Pavan WJ. Bocciardi R. Jan D. Neuron 1999. 150 Sakurai T. Hammer RE. Ballabio A. Lemort N. J Med Genet 1999. Lyonnet S. Milbrandt J.5:303-7. Emoto N.21:1291-302. GFRalpha1 is an essential receptor component for GDNF in the developing nervous system and kidney. Bolk S. Nat Genet 1996. Miyauchi T. Hum Mol Genet 1996. Kilkenny C. Wen D. Molecular characterization of endothelin receptors. 165 Southard-Smith EM. 135 Durbec P. and autonomic dysfunction. Masaki T. Henderson CE.22:201-3. de Wit D. Armanini MP.jmedgenet. Hum Mol Genet 1998.79:1277-85. The GDNF protein family: gene ablation studies reveal what they really do and how. Poulsen K. 136 Jing S. Vandlen R. Williams SC. Genomics 1998. Johnson EM. Goodman L. Amiel J. Kapur RP. Bidaud C. Johnson EM. J Med Genet 1995. Yanagisawa M.Hirschsprung disease. Hofstra R. Bachy B. Bonduelle M. Nature 1996.36:217-20. Marcos-Gutierrez CV. Salomon R. 134 Pichel JG. 162 Hofstra RM. Saarma M. 138 Rosenthal A. HoVer BJ.10:247–9. Casari G. Lampe PA. 146 Enomoto H. Ceccherini I. Novel mutations of the endothelin-B receptor gene in isolated patients with Hirschsprung’s disease. Priolo M.95:5161-5. Nature 1996. Salomon R. Goossens M. Attié-Bitach T. Trends Pharmacol Sci 1992.5:247-51. Heuckeroth RO. Simburger KS. Lira SA. Ballabio A. Hynes M.382:80-3. cardiac defects. Attie T. Forgie A. Frisen J. Hammer RE. Carpentieri ML. Fang M. 139 Kotzbauer PT. Tansey MG. Shen L. 144 Doray B. Creedon DJ. Pelet A. Wegner M. Pingault V. Tamir R. Baxevanis AD. Goddard A. de Sauvage F. Halushka M. Human GFRA1: cloning. Sherman D. Olson JM.5:347-9. supports multigenic inheritance in Hirschsprung disease. Richardson JA. Yanagisawa M. Snider WD. 163 Lane PW. and evaluation as a candidate gene for Hirschsprung disease susceptibility. Hagler K. Hermans-Borgmeyer I. Hamosh A. Yu Y. Hynes M. Pavan WJ. Van Roy B. 13:103-8. Staiano A. Phillips H. Nature 1996. Munnich A. Nishimura M. Association of 13q deletion and Hirschsprung’s disease. a novel neurotrophic factor related to GDNF and neurturin. Grinberg A. Proc Natl Acad Sci USA 1998. Kasuya Y. Pelet A. Tam P. Puliti A. Artemin. Eng C. Fornage M. Lyonnet S. Phillips HS.5:351-4. Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Hum Mol Genet 1996. A loss-of-function mutation in the endothelin-converting enzyme 1 (ECE-1) associated with Hirschsprung disease.381: 789-93.18:60-4.64:1216-21. Clouthier DE. Pollock RA. Leitner ML. Wang LC. Splitting a multigenic disease: segregation at three loci explains familial and population risk in Hirschsprung disease (in preparation). Cheung JC. Poulsen KT. Milbrandt J. Buys C. Davies JA. Fox GM. 153 Kiss P. 137 Treanor JJ. Proc Natl Acad Sci USA 1989. Reichardt LF.5:355-7. Nature 1996. Touraine R. Eng C. Altrock BW. Farrer LA. Holst PL. Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease. Edery P. Van Camp G. Gadd MA. Puri P. 161 Yanagisawa H. a novel member of the GDNF ligand family. Kos L.75:435-9. Stone DM. Pelet A. Johnson EM.14:341-4. Fahrner TJ. Chakravarti A. associated syndromes. Hu S. Luo Y. Munnich A. Meire F. Endothelin-B receptor mutations in patients with isolated Hirschsprung disease from a non-inbred population. 168 Southard-Smith EM. Simeoni J. Betsos N.26:793-4. Hirschsprung’s disease in a kindred: a possible clue to the genetics of the disease.32:531-6. Willems PJ. 167 Potterf SB. Hum Mol Genet 1996. Halushka M. Silos-Santiago I. and genetics 739 133 Sanchez MP. GFR alpha1-deﬁcient mice have deﬁcits in the enteric nervous system and kidneys. Double heterozygosity for a RET substitution interfering with splicing and an EDNRB missense mutation in Hirschsprung disease. Fox GM. a mouse model for human Hirschsprung disease.5:2023-6. Milbrandt J. Association of megacolon with a new dominant spotting gene (Dom) in the mouse. Arnheiter H. Nihoul-Fekete C.79:1267-76. Amiel J. Chakravarti A (group I).17:632-4. 159 Kusafuka T. Nature 1996. Neuron 1998. Yanagisawa M. Orsztovics M. 145 Cacalano G. Griseri P. Masaki T. Wang Y. Araki T.382: 73-6. Golden JP. Investigation of germline GFR -1 mutations in Hirschsprung disease. Sheng HZ. Araki T. Phillips HS. Hosoda K. Mutation of the RET ligand. Myers SM.20:245-53. Mulligan LM. Salomon R. Heuckeroth RO. Standaert L. 155 Baynash AG. Kuhlbrodt K. The Sox10 (Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome. neurturin. Kimura S. Davies A. Sox10 mutation disrupts neural crest development in Dom Hirschsprung mouse model. Rao VS. Rosenthal A. Suvanto P. Arch E. Eur J Hum Genet 1997. Louis JC. mapping. a relative of glial-cell-line-derived neurotrophic factor. Lampe PA. Neuron 1998. Salomon R. Ryan AM. Cupples R. Romeo G. He B. J Med Genet 1989. Neurturin. 164 Herbarth B. Fahrner TJ. Pediatr Radiol 1981. 148 Myers SM. Nat Genet 1998. Pavan WJ. Bonduelle M. Lampe PA. Osinga J. Lyonnet S. J Pediatr Surg 1982. Heuckeroth RO. Ponder B. 141 Baloh RH. Ellison JS. Takahashi M. Lee EJ. in Hirschsprung disease. GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha. Nihoul-Fekete C. de Sauvage FJ. Furumura M. 149 Inoue A. 166 Auricchio A. Attie T. Kroes H. Pachnis V.7:1449-52. Lyonnet S.48:354-62. Goto K. Richardson JA. 169 Bolk S. Liu HM. Defects in enteric innervation and kidney development in mice lacking GDNF. 154 Hosoda K. Handig I. Simburger KS. Lapchak PA. 152 Van Camp G. Vejsada R. Pelet A.107:1-6. Baynash AG. Baldwin CT. 140 Milbrandt J. Davies AM. Garces A. Buys CH. Billaud M. Moore M. Richardson JA. Read AP. 125:825-36. MoVat B.382:70-3. 157 Chakravarti A. Yanagisawa M. 170 Hall CM. Hum Mol Genet 1996. Endothelin receptor-mediated signaling in Hirschsprung disease. Valdenaire O. Tozzi A. Henderson CE.384:467-70. Dunn KJ. Emoto N. Cell 1994. Drago J. Granholm AC. Barbacid M. Angrist M. Beck CD. De novo mutation of GDNF. Golden JP. Leitner ML. Munnich A. genomic structure. Grigoriou M. Asai N. Genome Res 1999. Saarma M. Angrist M. Flori E. Kotzbauer PT. Lacombe D. Meijers C. Munnich A.85:1113-24. a novel receptor for GDNF. Giaid A. Mutation of the Sry-related Sox10 gene in dominant megacolon. Lyonnet S (group II). Nallasamy S. Farinas I. Cell 1994. J Hered 1984. Rosenthal A. Persephin. Klein RD. Neuron 1998. Enomoto H. Goessling A. Armanini M. Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice. Kato AC. Cell 1996. www. Gray C. Hefti F.9: 215-25. Milunsky A. Smith D. Staiano A. 147 Angrist M. Thompson H. Jackman A. Moore MW. Transcription factor hierarchy in Waardenburg syndrome: regulation of MITF expression by SOX10 and PAX3. Bentley K. Johnson EM. Chakravarti A. Van Thienen MN. Buj-Bello A. Pelet A. Johnson EM Jr. Hum Mol Genet 1996. Yanagisawa M.21:317-24. Chromosome 13q deletion with Waardenburg syndrome: further evidence for a gene involved in neural crest function on 13q. 142 Angrist M. Huang SP. Willems PJ. LoZer BM. supports peripheral and central neurons and signals through the GFRalpha3-RET receptor complex. 151 Cohen IT. Characterization of a multicomponent receptor for GDNF. 143 Ivanchuk SM. ligand for the RET/GDNFR-alpha receptor complex. Gray C. Jing S. Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. 160 Auricchio A. Wang LC. Vandlen R. 158 Amiel J.21:53-62. Development 1998.