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
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.
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.
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.
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
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.
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.
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.
Hirschsprung disease; Deafness; Sensorineural Hearing Loss; Hypoparathyroidism; HDR syndrome
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.
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.
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.
Hirschsprung's disease; constipation; colon
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.
Meconium plug; Hirschsprung’s disease; Cystic fibrosis
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.
We report the first case of an interstitial deletion of the distal long arm of chromosome 4 (q31.22----q34.2). The major clinical features are described and compared to those of other published reports of del 4q, mainly those sharing a common deleted segment with the present case (both interstitial and terminal). This comparison suggests that the characteristic phenotype attributed to terminal deletions of 4q31----qter probably mainly results from loss of the segment q31----q33-34.
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.
Five cases of the Hirschsprung's disease-congenital central
hypoventilation syndrome (CCHS) association are presented
and 41 other published cases reviewed. These children have a distinct pattern of associated features, an equal sex incidence, and a characteristic spectrum of disease severity which suggests that the
condition is genetically distinct from other cases of Hirschsprung's disease. While approximately 1.5% of Hirschsprung's disease patients, and 10% of those with total colonic aganglionosis, will have CCHS, up
to 50% of CCHS patients will have Hirschsprung's disease.
Approximately 20% of CCHS/Hirschsprung patients will also have
neuroblastoma or ganglioneuroma, usually multiple. Abnormalities of the
eye and autonomic nervous system are also common. The ventilatory abnormality is usually evident on the first day of life. The
aganglionosis is also severe, with more than half (59%) of the
patients having aganglionosis extending into the small bowel.
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.
DNA analysis; Hirschsprung's disease; multiple
endocrine neoplasia type 2A; RET
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.
SUBJECTS AND METHODS
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.
Hirschsprung disease; Diagnosis; Operative procedures; Laparoscopy; Surgical stomas
Three patients are described with different phenotypes and differing de novo interstitial deletions of the long arm of a chromosome 7. The first patient has a deletion with loss of the proximal 7q11.23 band. Only three other cases have been reported with this particular deletion. Our second case shows mild dysmorphism similar to the other four patients reported with deletion of bands 7q21.12----21.3. Our third patient has a deletion of the 7q22.1----32.2 segment and has many of the phenotypic features of the other reported cases of del 7q22----32. GUSB, the gene for beta-glucuronidase, has been localised to the 7cen----q22 region. Analysis of beta-glucuronidase levels in blood leucocytes of our patients has helped more precisely to assign this gene locus to 7q21.11 or 7q22.1.
Interstitial deletions of 6q are rare. We report a detailed clinical and molecular characterization of four patients with interstitial deletion involving 6q25. All of our patients presented with microcephaly, developmental delay, dysmorphic features and hearing loss, whereas two of them had agenesis of the corpus callosum. We determined the size, extent and genomic content of the deletions using high-density array-comparative genomic hybridization (a-CGH), and found that a common segment spanning 3.52 Mb within the 6q25.2–q25.3 region was deleted in all four cases. We hypothesize that a subset of genes in the commonly deleted region are dosage sensitive and that haploinsufficieny of these genes impairs normal development of the brain and hearing.
6q deletion; hearing loss; microcephaly, developmental delay; agenesis of the corpus callosum; array-CGH
On a review of 15 cases of Hirschsprung's disease of the colon we have encountered 4 cases of an atypical variant. These 4 cases had a zone of aganglionosis of both intermyenteric and submucous plexuses in the sigmoid colon and, in 1 case, a further zone of aganglionosis in the rectum. Ganglion cells reappeared distal to the sigmoid zone of aganglionosis. A transition zone was not invariably present. The clinical features demonstrated a variability of presentation typical of the more usual form of the disease. The importance of atypical Hirschsprung's disease is discussed from a diagnostic and pathogenetic viewpoint.
Hirschsprung’s disease is a congenital disorder that occurs in 1:5000 live births. It is characterised by an absence of enteric neurons along a variable region of the gastrointestinal tract. Hirschsprung’s disease is classified as a multigenic disorder, because the same phenotype is associated with mutations in multiple distinct genes. Furthermore, the genetics of Hirschsprung’s disease are highly complex and not strictly Mendelian. The phenotypic variability and incomplete penetrance observed in Hirschsprung’s disease also suggests the involvement of modifier genes. Here, we summarise the current knowledge of the genetics underlying Hirschsprung’s disease based on human and animal studies, focusing on the principal causative genes, their interactions, and the role of modifier genes.
Neural crest; Enteric nervous system; Hirschsprung’s disease; Aganglionosis; Modifier genes
Despite it has been reported that several loci are involved in Hirschsprung’s disease, the molecular basis of the disease remains yet essentially unknown. The study of collective properties of modules of functionally-related genes provides an efficient and sensitive statistical framework that can overcome sample size limitations in the study of rare diseases. Here, we present the extension of a previous study of a Spanish series of HSCR trios to an international cohort of 162 HSCR trios to validate the generality of the underlying functional basis of the Hirschsprung’s disease mechanisms previously found. The Pathway-Based Analysis (PBA) confirms a strong association of gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other processes related to the disease. In addition, network analysis recovers sub-networks significantly associated to the disease, which contain genes related to the same functionalities, thus providing an independent validation of these findings. The functional profiles of association obtained for patients populations from different countries were compared to each other. While gene associations were different at each series, the main functional associations were identical in all the five populations. These observations would also explain the reported low reproducibility of associations of individual disease genes across populations.
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.
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.
A method for the assay of vesical ganglion cells is described and the number and distribution of the neurones in three normal bladders was studied. Vesical ganglion counts were done in cases of the megaureter-megacystis syndrome, megaureter, bladder neck obstruction, megacystis associated with absent abdominal muscles, Hirschsprung's disease, and lumbar myelomeningocoele. A normal complement of neurones was found in each case.
No evidence was found that the megaureter-megacystis syndrome is due to an agenesis of the peripheral autonomic ganglia similar to that in Hirschsprung's disease. Vesical ganglia were normal in the two cases examined and no clinical association was found between the two conditions in a large series of cases. Moreover, a study of the cell counts suggests that at least some of the reports of such a lesion are based upon an inadequate appreciation of the number and distribution of neurones in the normal urinary tract.
The distinction between Hirschsprung's disease and idiopathic megacolon in childhood dates from the classic clinical, radiological, and histological studies of Bodian, Stephens, and Ward. This article describes clinical experience over 15 years of 94 patients in whom megacolon of these two types was recognised for the first time after the age of 10, to illustrate the problems of diagnosis and treatment in later years. Just as it is now recognised that patients with the clinical characteristics of Hirschsprung's disease may have one of several abnormalities of the myenteric plexus, including not only absence of ganglion cells, but also patchy or zonal loss, abnormal neurones or neuronal dysplasia, so idiopathic megacolon may also be a heterogeneous group of cases. This paper suggests on clinical grounds that those patients with idiopathic megacolon whose symptoms start in childhood differ from those whose symptoms develop in later years.