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1.  Current significance of meconium plug syndrome 
Journal of pediatric surgery  2008;43(5):896-898.
The significance of meconium plug syndrome is dependent on the underlying diagnosis. The incidence of pathologic finding, particularly Hirschsprung’s disease, contributing to the presence of these plugs, has been debated. However, there are little recent data in the literature. Therefore, we reviewed our experience with meconium plugs as a cause of abdominal distension to evaluate the associated conditions and incidence of Hirschsprung’s disease.
We reviewed the records of newborns with meconium plugs found in the distal colon on contrast enema from 1994 to 2007. Demographics, radiologic findings, histologic findings, operative findings, and clinical courses were reviewed.
During the study period, 77 patients were identified. Mean gestational age was 37.4 weeks and birth weight, 2977 g. Hirschsprung’s disease was found in 10 patients (13%). One had ultrashort segment disease and another had total colonic aganglionosis. Maternal diabetes was identified in 6 patients. No patients were diagnosed with cystic fibrosis, meconium ileus, malrotation, or intestinal atresia.
Meconium plugs found on contrast enema are associated with a 13% incidence of Hirschsprung’s disease in our experience. Although all patients with plugs and persistent abnormal stooling patterns should prompt a rectal biopsy and genetic probe, the incidence of Hirschsprung’s and cystic fibrosis may not be as high as previously reported.
PMCID: PMC3086204  PMID: 18485962
Meconium plug; Hirschsprung’s disease; Cystic fibrosis
2.  A Hirschsprung disease locus at 22q11? 
Journal of Medical Genetics  1999;36(3):221-224.
We report a boy with truncus arteriosus, dysmorphic features, developmental delay, passing hypotonia, short segment Hirschsprung disease (HSCR), and paroxysmal hypoventilation. FISH analysis showed an interstitial deletion in chromosome band 22q11.2 coinciding with the deletions found in DiGeorge syndrome and velocardiofacial syndrome. Mutation scanning of RET, GDNF, EDNRB, and EDN3, genes associated with Hirschsprung disease, showed no aberrations. Since we know of two more patients with velocardiofacial syndrome and HSCR, we hypothesise that a gene responsible for proper development of the enteric nervous system may be included in the 22q11.2 region.

Keywords: CATCH 22; Hirschsprung disease; hypoventilation
PMCID: PMC1734323  PMID: 10204849
3.  Hirschsprung disease, microcephaly, mental retardation, and characteristic facial features: delineation of a new syndrome and identification of a locus at chromosome 2q22-q23. 
Journal of Medical Genetics  1998;35(8):617-623.
We have identified six children with a distinctive facial phenotype in association with mental retardation (MR), microcephaly, and short stature, four of whom presented with Hirschsprung (HSCR) disease in the neonatal period. HSCR was diagnosed in a further child at the age of 3 years after investigation for severe chronic constipation and another child, identified as sharing the same facial phenotype, had chronic constipation, but did not have HSCR. One of our patients has an interstitial deletion of chromosome 2, del(2)(q21q23). These children strongly resemble the patient reported by Lurie et al with HSCR and dysmorphic features associated with del(2)(q22q23). All patients have been isolated cases, suggesting a contiguous gene syndrome or a dominant single gene disorder involving a locus for HSCR located at 2q22-q23. Review of published reports suggests that there is significant phenotypic and genetic heterogeneity within the group of patients with HSCR, MR, and microcephaly. In particular, our patients appear to have a separate disorder from Goldberg-Shprintzen syndrome, for which autosomal recessive inheritance has been proposed because of sib recurrence and consanguinity in some families.
PMCID: PMC1051383  PMID: 9719364
4.  Molecular Mechanisms Generating and Stabilizing Terminal 22q13 Deletions in 44 Subjects with Phelan/McDermid Syndrome 
PLoS Genetics  2011;7(7):e1002173.
In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17–74 kb in 9% of the patients. Haploinsufficiency of the SHANK3 gene, confirmed in all rearrangements, is very likely the cause of the major neurological features associated with PMS. SHANK3 mutations can also result in language and/or social interaction disabilities. We determined the breakpoint junctions in 29 cases, providing a realistic snapshot of the variety of mechanisms driving non-recurrent deletion and repair at chromosome ends. De novo telomere synthesis and telomere capture are used to repair terminal deletions; non-homologous end-joining or microhomology-mediated break-induced replication is probably involved in ring 22 formation and translocations; non-homologous end-joining and fork stalling and template switching prevail in cases with interstitial 22q13.3. For the first time, we also demonstrated that distinct stabilizing events of the same terminal deletion can occur in different early embryonic cells, proving that terminal deletions can be repaired by multistep healing events and supporting the recent hypothesis that rare pathogenic germline rearrangements may have mitotic origin. Finally, the progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS.
Author Summary
Terminal chromosome deletions are among the most commonly observed rearrangements detected by cytogenetics and may result in several well-known genetic syndromes. We used 22q13 deletions to study how these types of chromosome abnormalities arise. Children with Phelan/McDermid syndrome, caused by deletion of the terminal portion of chromosome 22, experience developmental delay, absent or severely delayed speech, and frequent behavioral problems. Lack of one copy of SHANK3, a key gene for the correct development and organization of brain synapses, is very likely the basis of the syndrome's major neurological features. Deletion of additional genes probably causes more complex phenotypes in subjects with larger deletions. We also studied patients who only lack a portion of SHANK3 and demonstrated that small, hard-to-detect deletions of this gene may cause substantial clinical problems. Until now, the 22q distal deletion had been only diagnosed in very young people. We studied a large group of patients of different ages and discovered that all adult patients face progressive cognitive decline. Our study demonstrates that deletion of the terminal portion of chromosome 22, a prototype for terminal deletions in human chromosomes, can occur in several ways. Mosaic deletions of different size can also form in early embryogenesis.
PMCID: PMC3136441  PMID: 21779178
5.  Rectal biopsy for diagnosis of intestinal neuronal dysplasia in children: a prospective multicentre study on interobserver variation and clinical outcome 
Gut  1999;44(6):853-861.
BACKGROUND—Intestinal neuronal dysplasia (IND) of the colonic submucous plexus is considered to be a congenital malformation of the enteric nervous system causing symptoms resembling those of Hirschsprung's disease. In contrast with the established diagnosis of aganglionosis using enzyme histochemistry, controversy exists over the diagnostic criteria of IND on rectal biopsies previously defined by a consensus report and the causal relation between morphological findings and clinical symptoms.
AIMS—The interobserver variability was prospectively investigated with respect to final diagnoses and several histological features in rectal biopsy specimens from children suspected of having colonic motility disturbances.
METHODS—377 biopsy specimens from 108 children aged 4 days to 15 years were independently coded without knowledge of clinical symptoms by three experienced pathologists for 20 histological features, and a final diagnosis was given for every case. Interobserver variation for the different items and the final diagnosis were analysed using Cohen's κ statistic. Clinical data at biopsy and outcome after 12 months were related to morphological findings.
RESULTS—The three pathologists agreed completely with respect to the diagnosis Hirschsprung's disease (κ = 1), but in only 14% of the children without aganglionosis. In 15 (17%) of the 87 children without aganglionosis, at least one pathologist judged the case as normal, while another diagnosed IND. κ values were close to the zero value expected by chance for the diagnoses normal and IND. Young age was related to the presence of several morphological features—for example, acetylcholine esterase staining and presence of giant ganglia. Children with chronic constipation diagnosed as having IND, given no other specific diagnosis by any of the pathologists, were significantly younger (median 8.8 months) and had a higher cure rate after one year (60%) than constipated patients considered by all observers to have no histological abnormalities (median 6.1 years, cure rate 23%).
CONCLUSIONS—In contrast with Hirschsprung's disease, there is a high interobserver variation with regard to the different morphological features and final diagnosis of IND, based on the criteria and conditions of the previous consensus report. The high frequency of histological "abnormalities" in young infants suggests that some of the features may represent a normal variant of postnatal development rather than a pathological process. Investigations using more refined and morphometric methods in rectal specimens from infants and children without bowel disease are needed to define the normal range of morphological appearance at different ages. These preliminary data indicate that, with current knowledge, rectal biopsy for diagnostic purposes should only be performed in constipated children for diagnosis of Hirschsprung's disease.

Keywords: intestinal neuronal dysplasia; Hirschsprung's disease; constipation; enzyme histochemistry
PMCID: PMC1727546  PMID: 10323889
6.  Critical region in 2q31.2q32.3 deletion syndrome: Report of two phenotypically distinct patients, one with an additional deletion in Alagille syndrome region 
Standard cytogenetic analysis has revealed to date more than 30 reported cases presenting interstitial deletions involving region 2q31-q32, but with poorly defined breakpoints. After the postulation of 2q31.2q32.3 deletion as a clinically recognizable disorder, more patients were reported with a critical region proposed and candidate genes pointed out.
We report two female patients with de novo chromosome 2 cytogenetically visible deletions, one of them with an additional de novo deletion in chromosome 20p12.2p12.3. Patient I presents a 16.8 Mb deletion in 2q31.2q32.3 while patient II presents a smaller deletion of 7 Mb in 2q32.1q32.3, entirely contained within patient I deleted region, and a second 4 Mb deletion in Alagille syndrome region. Patient I clearly manifests symptoms associated with the 2q31.2q32.3 deletion syndrome, like the muscular phenotype and behavioral problems, while patient II phenotype is compatible with the 20p12 deletion since she manifests problems at the cardiac level, without significant dysmorphisms and an apparently normal psychomotor development.
Whereas Alagille syndrome is a well characterized condition mainly caused by haploinsufficiency of JAG1 gene, with manifestations that can range from slight clinical findings to major symptoms in different domains, the 2q31.2q32.3 deletion syndrome is still being delineated. The occurrence of both imbalances in reported patient II would be expected to cause a more severe phenotype compared to the individual phenotype associated with each imbalance, which is not the case, since there are no manifestations due to the 2q32 deletion. This, together with the fact that patient I deleted region overlaps previously reported cases and patient II deletion is outside this common region, reinforces the existence of a critical region in 2q31.3q32.1, between 181 to 185 Mb, responsible for the clinical phenotype.
PMCID: PMC3460744  PMID: 22550961
2q31.2q32.3 deletion; Critical region; Alagille syndrome
7.  A consanguineous family with Hirschsprung disease, microcephaly, and mental retardation (Goldberg-Shprintzen syndrome) 
Journal of Medical Genetics  1999;36(6):485-489.
Hirschsprung disease, mental retardation, microcephaly, and specific craniofacial dysmorphism were observed in three children from a large, consanguineous, Moroccan family. A fourth child showed similar clinical features, with the exception of Hirschsprung disease. The association of these abnormalities in these children represents the Goldberg-Shprintzen syndrome (OMIM 235730).
  Mutation scanning of genes potentially involved in Hirschsprung disease, RET, GDNF, EDN3, and EDNRB, showed a sequence variant, Ser305Asn, in exon 4 of the EDNRB gene in the index patient of this family. The Ser305Asn substitution present in two of the four patients and four healthy relatives and absent in one of the remaining two patients illustrates the difficulties in interpreting the presence of mutations in families with Hirschsprung disease. It is unlikely that the EDNRB variant contributes to the phenotype. This consanguineous family might be useful for the identification of a Goldberg-Shprintzen locus.

Keywords: Hirschsprung disease; microcephaly; mental retardation; EDNRB variant
PMCID: PMC1734390  PMID: 10874640
8.  Oncological implications of RET gene mutations in Hirschsprung's disease 
Gut  1998;43(4):542-547.
Background—Germline mutations of the RET proto-oncogene identical to those found in the tumour predisposition syndrome multiple endocrine neoplasia type 2A (MEN2A), were detected in 2.5-5% of sporadic and familial cases of Hirschsprung's disease. Some patients with Hirschsprung's disease may therefore be exposed to a highly increased risk of tumours. 
Aims—To define clinical use of RET gene testing in Hirschsprung's disease and related patient management from an oncological point of view. 
Methods—Sixty patients with Hirschsprung's disease were screened for RET mutations. In three, MEN2A type RET mutations were detected. Case reports for these three patients are presented. 
Results and conclusions—Only 22 families or sporadic patients with Hirschsprung's disease and MEN2A type RET mutations have been reported. Therefore, it is difficult to predict tumour risk for patients with familial or sporadic Hirschsprung's disease, and their relatives, who carry these mutations. For these mutation carriers, periodic screening for tumours as in MEN2A is advised, but prophylactic thyroidectomy is offered hesitantly. RET gene testing in familial or sporadic Hirschsprung's disease is not recommended at present outside a complete clinical research setting. In combined MEN2A/Hirschsprung's disease families RET gene testing, tumour screening, and prophylactic thyroidectomy are indicated as in MEN2A. 

Keywords: DNA analysis; Hirschsprung's disease; multiple endocrine neoplasia type 2A; RET
PMCID: PMC1727297  PMID: 9824583
9.  Umbilical cord ulceration in association with intestinal atresia in a child with deletion 13q and Hirschsprung's disease. 
The case is reported of a baby boy with an interstitial deletion of the long arm of chromosome 13 who, in addition to the described associations of Hirschsprung's disease and intestinal atresia, had umbilical cord ulceration resulting in massive intrapartum haemorrhage. This case provides support for the existence of a previously reported association between umbilical cord ulceration and intestinal atresia, and suggests that it is aetiologically heterogeneous.
PMCID: PMC1061129  PMID: 7820720
10.  Molecular analysis of three patients with interstitial deletions of chromosome band 14q31. 
Journal of Medical Genetics  1995;32(7):564-567.
Two patients and one three generation family with interstitial deletions of distal chromosome band 14q31 are described. The deletions were initially identified by chromosome analysis; we have used highly informative simple sequence repeat polymorphisms to define the deletions at the molecular level. This analysis also establishes the parental origin of the deleted chromosome. One of the patients was initially described as having a terminal deletion of chromosome 14 from 14q31 to 14qter; we show here that this child has instead an interstitial deletion of band 14q31. The smallest deletion involves a single anonymous DNA marker and is associated with an almost normal phenotype. The two patients with larger deletions have phenotypes similar to those seen in previously described cases of interstitial deletions of chromosome 14, including minor dysmorphic features and developmental delay. Delineation of these deletions allows the ordering of markers within the 14q31 region, in which the gene for the degenerative neurological disorder Machado-Joseph disease is localised.
PMCID: PMC1050554  PMID: 7562974
11.  Genome-Wide Copy Number Analysis Uncovers a New HSCR Gene: NRG3 
PLoS Genetics  2012;8(5):e1002687.
Hirschsprung disease (HSCR) is a congenital disorder characterized by aganglionosis of the distal intestine. To assess the contribution of copy number variants (CNVs) to HSCR, we analysed the data generated from our previous genome-wide association study on HSCR patients, whereby we identified NRG1 as a new HSCR susceptibility locus. Analysis of 129 Chinese patients and 331 ethnically matched controls showed that HSCR patients have a greater burden of rare CNVs (p = 1.50×10−5), particularly for those encompassing genes (p = 5.00×10−6). Our study identified 246 rare-genic CNVs exclusive to patients. Among those, we detected a NRG3 deletion (p = 1.64×10−3). Subsequent follow-up (96 additional patients and 220 controls) on NRG3 revealed 9 deletions (combined p = 3.36×10−5) and 2 de novo duplications among patients and two deletions among controls. Importantly, NRG3 is a paralog of NRG1. Stratification of patients by presence/absence of HSCR–associated syndromes showed that while syndromic–HSCR patients carried significantly longer CNVs than the non-syndromic or controls (p = 1.50×10−5), non-syndromic patients were enriched in CNV number when compared to controls (p = 4.00×10−6) or the syndromic counterpart. Our results suggest a role for NRG3 in HSCR etiology and provide insights into the relative contribution of structural variants in both syndromic and non-syndromic HSCR. This would be the first genome-wide catalog of copy number variants identified in HSCR.
Author Summary
Copy number variations (CNVs) are significant genetic risk factors in disease pathogenesis and represent an important portion of missing heritability for some human diseases, making their discovery essential for the identification of genes and risk factors for a wide range of diseases, including Hirschsprung disease (HSCR, congenital colon aganglionosis). Since the discovery of the major HSCR gene, RET, a number of rare mutations have been reported in RET and other genes involved in the development of the enteric nervous system. However, these mutations contribute to only a small proportion of the disease susceptibility. Taking advantage of the recent technical and methodological advances, we have examined the contribution of CNVs to the disease. We have found that HSCR patients are enriched with CNVs encompassing genes. In particular, we found that deletions of NRG3, a paralog of the previously identified HSCR–susceptibility gene NRG1, were associated with the HSCR phenotype.
PMCID: PMC3349728  PMID: 22589734
12.  Partial monosomy 7 with interstitial deletions in two infants with differing congenital abnormalities. 
Journal of Medical Genetics  1979;16(6):453-460.
Two cases of interstitial deletion of chromosome 7 are presented, one involving the short arm and the other the long arm. The cytogenetic, dermatoglyphic, and clinical findings are compared with previously reported cases of chromosome 7 deletion. The patient with a short arm deletion differs clinically from the previously reported cases but, in common with a least one previous case, has a low total finger ridge count. His interstitial deletion involving the 7p13 leads to 7p21 region also differs from 7p deletions reported in earlier cases. The patient with a long arm deletion has an interstitial loss of the region between 7q11 and 7q21, corresponding to one of three groups of 7q deletion that have been recognised. The phenotypic changes in this group are less well defined than in the other two and the patient presented here differs clinically from the previously reported cases, apart from one phenotypically normal mosaic case, in lacking morphological abnormalities. He shares with one previous case both epilepsy and a high intensity of dermal ridge patterns.
PMCID: PMC1012593  PMID: 537019
13.  Complex pathogenesis of Hirschsprung's disease in a patient with hydrocephalus, vesico-ureteral reflux and a balanced translocation t(3;17)(p12;q11) 
Hirschsprung's disease (HSCR), a congenital complex disorder of intestinal innervation, is often associated with other inherited syndromes. Identifying genes involved in syndromic HSCR cases will not only help understanding the specific underlying diseases, but it will also give an insight into the development of the most frequent isolated HSCR. The association between hydrocephalus and HSCR is not surprising as a large number of patients have been reported to show the same clinical association, most of them showing mutations in the L1CAM gene, encoding a neural adhesion molecule often involved in isolated X-linked hydrocephalus. L1 defects are believed to be necessary but not sufficient for the occurrence of the intestinal phenotype in syndromic cases. In this paper, we have carried out the molecular characterization of a patient affected with Hirschsprung's disease and X-linked hydrocephalus, with a de novo reciprocal balanced translocation t(3;17)(p12;q21). In particular, we have taken advantage of this chromosomal defect to gain access to the predisposing background possibly leading to Hirschsprung's disease. Detailed analysis of the RET and L1CAM genes, and molecular characterization of MYO18A and TIAF1, the genes involved in the balanced translocation, allowed us to identify, besides the L1 mutation c.2265delC, different additional factors related to RET-dependent and -independent pathways which may have contributed to the genesis of enteric phenotype in the present patient.
PMCID: PMC2986215  PMID: 19300444
Hirschsprung's disease; Hydrocephalus; RET; L1CAM; TIAF1
14.  Evolution in the management of Hirschsprung’s disease in the UK and Ireland: a national survey of practice revisited 
The management of Hirschsprung’s disease continues to evolve. This questionnaire survey aimed to determine current surgical management strategies for Hirschsprung’s disease in Britain.
The survey was sent electronically to all British paediatric surgeons. Initial questions explored individual experience and regional service provision. Additional questions, reserved for surgeons who perform definitive Hirschsprung’s disease surgery, addressed specific clinical scenarios.
Surveys were sent to 142 surgeons yielding 85 responses. After exclusions, 64 surveys from 21 centres were analysed. Forty-seven respondents worked in centres with designated ‘Hirschsprung’s disease surgeons’. Forty respondents perform definitive Hirschsprung’s disease surgery. In a well neonate with left-sided Hirschsprung’s disease, 34 of 40 surgeons favour primary pull-through following bowel decompression with rectal washouts; 35 of 40 surgeons aim to perform definitive surgery at less than 3 months of age, with 17 favouring laparoscopic-assisted Soave–Boley and 15 favouring an open Duhamel pull-through. Of the 40 surgeons, 36 use a staged approach to right-sided/total colonic Hirschsprung’s disease with 23 favouring a Duhamel or Long Duhamel pull-through.
The primary pull-through, using an open Duhamel or laparoscopic-assisted Soave–Boley technique, during the first 3 months of life, has become the operative strategy of choice in rectosigmoid Hirschsprung’s disease in Britain. Marked variation in practice remains for right-sided Hirschsprung’s disease.
PMCID: PMC3293269  PMID: 20738896
Hirschsprung disease; Diagnosis; Operative procedures; Laparoscopy; Surgical stomas
15.  Coarctation of the aorta and mild to moderate developmental delay in a child with a de novo deletion of chromosome 15(q21.1q22.2) 
Deletion of 15q21q22 is a rare chromosomal anomaly. To date, there have been nine reports describing ten individuals with different segmental losses involving 15q21 and 15q22. Many of these individuals have common features of growth retardation, hypotonia and moderate to severe mental retardation. Congenital heart disease has been described in three individuals with interstitial deletion involving this region of chromosome 15.
Case presentation
We report a child with coarctation of the aorta, partial agenesis of corpus callosum and mild to moderate developmental delay, with a de novo deletion of 15q21.1q22.2, detected by the array Comparative Genomic Hybridization (CGH). We utilized chromosome 15-specific microarray-based CGH to define the chromosomal breakpoints in this patient.
This is the first description of mapping of an interstitial deletion involving the chromosome 15q21q22 segment using the chromosome 15-specific array-CGH. The report also expands the spectrum of clinical phenotype associated with 15q21q22 deletion.
PMCID: PMC1397801  PMID: 16472378
16.  Hyperganglionosis mimicking Hirschsprung's disease. 
Archives of Disease in Childhood  1991;66(11):1300-1303.
Three patients with hyperganglionosis are reported in whom an initial diagnosis of Hirschsprung's disease was suspected. In one patient there was a classic presentation with constipation, in another Hirschsprung's disease coexisted, and in the third the initial inadequate suction rectal biopsy specimen was suggestive of Hirschsprung's disease on acetylcholinesterase staining. Evidence of hypertrophy and hyperplasia of the intermuscular and submucosal plexuses on a full thickness bowel biopsy specimen was used to confirm the diagnosis of hyperganglionosis, suggested by the characteristic demonstration of moderate increase in the number of acetylcholinesterase stained nerve fibres in the lamina propria mucosae on rectal biopsy. Surgical management was guided by clinical signs. Two patients had colonic resections; the third had temporary stomal diversion. Hyperganglionosis is rarer than Hirschsprung's disease but is known to mimic it. We suggest full thickness bowel specimens are needed to confirm the diagnosis and that inadequate rectal suction biopsies must be interpreted with caution.
PMCID: PMC1793294  PMID: 1755642
17.  HDR Syndrome (Hypoparathyroidism, Sensorineural Deafness and Renal Disease) Accompanied by Hirschsprung Disease 
Iranian Journal of Pediatrics  2010;20(1):123-126.
HDR syndrome (hypoparathyroidism, sensorineural deafness and renal disease) is an autosomal dominant condition, defined by the triad hypoparathyroidism, renal dysplasia and hearing loss. Hirschsprung (HSCR) disease is a variable congenital absence of ganglion cells of the enteric nervous system resulting in degrees of functional bowel obstruction. Rarer chromosomal anomalies are reported in combination with Hirschsprung disease like DiGeorge syndrome, mosaic trisomy 8, XXY chromosomal constitution, partial duplication of chromosome 2q, tetrasomy 9p, and 20p deletion.
Case Presentation
Here, we describe an 8 year-old girl with HDR syndrome accompanied by Hirschsprung disease. Although the association of Hirschsprung disease with chromosomal anomalies has been reported, according to our knowledge, this is the first report of associated HSCR with HDR syndrome.
PMCID: PMC3446003  PMID: 23056694
Hirschsprung disease; Deafness; Sensorineural Hearing Loss; Hypoparathyroidism; HDR syndrome
18.  Screening of MITF and SOX10 Regulatory Regions in Waardenburg Syndrome Type 2 
PLoS ONE  2012;7(7):e41927.
Waardenburg syndrome (WS) is a rare auditory-pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and pigmentation defects. Four subtypes are clinically defined based on the presence or absence of additional symptoms. WS type 2 (WS2) can result from mutations within the MITF or SOX10 genes; however, 70% of WS2 cases remain unexplained at the molecular level, suggesting that other genes might be involved and/or that mutations within the known genes escaped previous screenings. The recent identification of a deletion encompassing three of the SOX10 regulatory elements in a patient presenting with another WS subtype, WS4, defined by its association with Hirschsprung disease, led us to search for deletions and point mutations within the MITF and SOX10 regulatory elements in 28 yet unexplained WS2 cases. Two nucleotide variations were identified: one in close proximity to the MITF distal enhancer (MDE) and one within the U1 SOX10 enhancer. Functional analyses argued against a pathogenic effect of these variations, suggesting that mutations within regulatory elements of WS genes are not a major cause of this neurocristopathy.
PMCID: PMC3407046  PMID: 22848661
19.  A prospective observational study of associated anomalies in Hirschsprung’s disease 
Associated anomalies have been reported in around 20% of Hirschsprung patients but many Authors suggested a measure of underestimation. We therefore implemented a prospective observational study on 106 consecutive HSCR patients aimed at defining the percentage of associated anomalies and implementing a personalized and up-to-date diagnostic algorithm.
After Institutional Ethical Committee approval, 106 consecutive Hirschsprung patients admitted to our Institution between January 2010 and December 2012 were included. All families were asked to sign a specific Informed Consent form and in case of acceptance each patient underwent an advanced diagnostic algorithm, including renal ultrasound scan (US), cardiologic assessment with cardiac US, cerebral US, audiometry, ENT and ophthalmologic assessments plus further specialist evaluations based on specific clinical features.
Male to female ratio of our series of patients was 3,4:1. Aganglionosis was confined to the rectosigmoid colon (classic forms) in 74,5% of cases. We detected 112 associated anomalies in 61 (57,5%) patients. The percentage did not significantly differ according to gender or length of aganglionosis. Overall, 43,4% of patients complained ophthalmologic issues (mostly refraction anomalies), 9,4% visual impairment, 20,7% congenital anomalies of the kidney and urinary tract, 4,7% congenital heart disease, 4,7% hearing impairment or deafness, 2,3% central nervous system anomalies, 8,5% chromosomal abnormalities or syndromes and 12,3% other associated anomalies.
Our study confirmed the underestimation of certain associated anomalies in Hirschsprung patients, such as hearing impairment and congenital anomalies of the kidney and urinary tract. Subsequently, based on our results we strongly suggest performing renal US and audiometry in all patients. Conversely, ophthalmologic assessment and cerebral and heart US can be performed according to guidelines applied to the general population or in case of patients with suspected clinical features or chromosomal abnormalities. This updated diagnostic algorithm aims at improving overall outcome thanks to better prognostic expectations, prevention strategies and early rehabilitation modalities. The investigation of genetic background of patients with associated anomalies might be the next step to explore this intriguing multifactorial congenital disease.
PMCID: PMC4222065  PMID: 24267509
Hirschsprung; Phenotype; Observational study; Associated anomalies
20.  HIRSCHSPRUNG'S DISEASE—The Clinical Differentiation and Treatment of Children with Hirschsprung's Disease and Pseudo-Hirschsprung's Disease 
California Medicine  1958;89(1):7-13.
Hirschsprung's disease is marked by constipation from the time of birth, with the development, if uncorrected, of a protuberant abdomen and flared costal margins. The rectal ampulla is empty and the abdomen is filled with fecal masses. Pain is not prominent. Flatus is passed in large amounts. Encopresis does not occur. Barium enema shows the characteristic narrowed distal rectal segment and biopsy of the rectum shows absence of the ganglion cells of the myenteric plexus.
Treatment is operative resection of the distal narrow segment and a primary anastomosis.
Hirschsprung's disease may be mimicked in children with:
1. Psychogenic constipation—pseudo-Hirschsprung's disease. Unlike Hirschsprung's disease, symptoms do not appear at birth, encopresis is common, and the barium enema shows no narrow distal segment.
2. Mental retardation and cerebral defect.
3. Corrected imperforate anus—on the basis of stenosis, imperfect innervation or poor habit training.
4. Cretinism—with severe constipation and intestinal dilatation perhaps the presenting symptoms.
Treatment of these four groups of children with severe constipation not due to Hirschsprung's disease is:
For Group 1, open discussion with parent and child. Assumption by the physician of full control of the details of treatment, and relegation of parent to the role of the physician's agent in following the prescribed regimen.
For Group 2, an enema regimen. Whereas fairly rapid restoration (and then persistence) of normal bowel habit can be expected in Group 1, the basic defects in Group 2 may require indefinite continuation of treatment.
For Group 3, regular enema regimen, in the less severe cases—one identical with that used in Group 1, and dilatation of strictures or anoplasty.
In Group 4, thyroid hormone therapy relieves the constipation of hypothyroidism and causes reversion of radiographic changes in the colon and rectum.
PMCID: PMC1512951  PMID: 13561108
21.  Hirschsprung's Disease: A Review 
Canadian Family Physician  1986;32:1521-1523.
Constipation is a common symptom in infants and young children who are seen by primary care physicians. If a patient fails to respond to the appropriate medical therapy for constipation, then the physician should consider the possibility of Hirschsprung's disease, a congenital disease in which ganglion cells are absent from the distal gastrointestinal tract, and which results in a functional colonic obstruction. Early diagnosis and prompt treatment of Hirschsprung's disease will result in a significantly improved quality of life for the patient, and may alleviate potentially life-threatening complications. This article describes a case of Hirschsprung's disease and reviews the most current literature on the topic. Clinical features that distinguish Hirschsprung's disease from other causes of constipation are emphasized.
PMCID: PMC2327428  PMID: 21267104
Hirschsprung's disease; constipation; colon
22.  Chromosome 13q deletion with Waardenburg syndrome: further evidence for a gene involved in neural crest function on 13q. 
Journal of Medical Genetics  1995;32(7):531-536.
Waardenburg syndrome (WS) is an autosomal dominant disorder characterised by pigmentary abnormalities and sensorineural deafness. It is subcategorised into type 1 (WS1) and type 2 (WS2) on the basis of the presence (WS1) or absence (WS2) of dystopia canthorum. WS1 is always caused by mutations in the PAX3 gene, whereas WS2 is caused by mutations in the microphthalmia (MITF) gene in some but not all families. An association of WS symptoms with Hirschsprung disease (HSCR) has been reported in many families. We report here a patient with characteristics of WS2 and a de novo interstitial deletion of chromosome 13q. We also describe a family with two sibs who have both WS2 and HSCR. In this family, all possible genes for WS and HSCR, but not chromosome 13q, could be excluded. As an association between chromosome 13q and HSCR/WS has been reported previously, these data suggest that there is a gene on chromosome 13q that is responsible for WS or HSCR or both.
PMCID: PMC1050545  PMID: 7562965
23.  ‘Hop the skip’ with extended segment intestinal biopsy in Hirschsprung's disease 
Skip segment Hirschsprung's is an extremely rare condition, with only 25 reported cases in the English language literature. Diagnosis of skip segment Hirschsprung's may be missed as it is rarely suspected at initial surgery.
A case report of an infant with total colonic aganglionosis and a skip segment Hirschsprung's in the cecum is presented. A review of literature on current surgical practice is presented along with our suggested modification to the diagnostic and therapeutic algorithm of this rare condition.
In our patient the initial leveling colostomy was incorrectly sited at the level of the first detected ganglionated segment. Subsequent recurrent episodes of enterocolitis led to a diagnosis of a long skip segment involving the ascending colon, cecum and terminal ileum. Correct leveling colostomy and a subsequent Duhamel procedure led to a good outcome.
Determination of the transition zone in Hirschsprung's may be incorrect if intestinal biopsies are terminated at the first evidence of ganglion cells. Extended segment intestinal biopsies should be included in the algorithm for management of long segment Hirschsprung's disease and will enable the surgeon to correctly detect rare manifestations such as skip segment disease at the initial procedure.
PMCID: PMC3316769  PMID: 22449568
Hirschsprung's disease; Skip-segment; Biopsy
24.  High resolution mapping of interstitial long arm deletions of chromosome 16: relationship to phenotype. 
Journal of Medical Genetics  1993;30(10):828-832.
The breakpoints of seven interstitial deletions of the long arm of chromosome 16 and two ring chromosomes of this chromosome were mapped by in situ hybridisation or by analysis of mouse/human somatic cell hybrids containing the deleted chromosome 16. Use of a high resolution cytogenetic based physical map of chromosome 16 enabled breakpoints to be assigned to an average resolution of at least 1.6 Mb. In general, interstitial deletions involving q12 or q22.1 have broadly similar phenotypes though there are differences in specific abnormalities. Deletions involving regions more distal, from 16q22.1 to 16q24.1, were associated with relatively mild dysmorphism. One region of the long arm, q24.2 to q24.3, was not involved in any deletion, either in this study or in any previous report. Presumably, monosomy for this region is lethal. In contrast, patients with deletions of 16q21 have a normal phenotype. These results are consistent with the proposed distribution of genes, frequent in telomeric Giesma light band regions but infrequent in G positive bands.
PMCID: PMC1016564  PMID: 8230159
25.  Hirschsprung's disease: genetic mutations in mice and men 
Gut  1997;41(4):436-441.
MRC Brain Development Programme,Department of Developmental Neurobiology,UMDS Guy's Hospital,London SE1 9RT, UK
Hirschsprung's disease is a neuronal dysplasia of the hindgut, characterised by a loss of neurones, which affects about 1in 5000 live births.1 Genetic factors have been implicated in the aetiology of this disease in about 20% of cases and a dominant pattern of inheritance has been revealed in several families. The pathogenesis of the aganglionosis is often attributed to a failure of migration of neural crest cells, although this has not been proven. 
Recently, mutations in a developmentally regulated receptor tyrosine kinase gene, ret, and mutations in the endothelin receptor-B gene (ENDR-B) have both been linked to familial Hirschsprung's disease in humans.4-6 Moreover, certain mutant mouse strains—namely piebald lethal and lethal spotted—exhibit striking similarities to the human condition. The mutation which gives rise to piebald lethal has now been found to be in the ENDR-B gene,7 and the mutation associated with lethal spotted occurs in the gene for endothelin-3 (ET-3), a ligand for ENDR-B.8 
Two transgenic mouse lines have been developed which also reflect the human disease: ret-k , which has a loss of function mutation of the ret gene,9 and ENDR-B null.10 In addition, the introduction of a Lac-Z reporter gene into neural crest cells of aganglionic mice has made it possible to study directly the fate of enteric neuroblasts which are affected by "Hirschsprung's-like" mutations.11 Here, we review the possible roles of RET and endothelin in the normal development of the enteric nervous system, and the significance of their mutated forms in the pathogenesis of familial aganglionosis. 
This review focuses on recent advances in our understanding of the genetic basis of the lesions which have been implicated in congenital forms of Hirschsprung's disease. Disruption of these genes in the mouse, either by transgenic "knockout" approaches or in mutant mouse lines, offers the prospect of greater understanding of both the cellular and developmental bases of the human disease. 

PMCID: PMC1891517  PMID: 9391239

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