Accuracy of colonic mucosal patterns at contrast enema for diagnosis of Hirschsprung disease.

BACKGROUND: Various patterns of colonic mucosal irregularity have been recorded on contrast enema, each with individually very low sensitivity, but high specificity. OBJECTIVE: To assess the accuracy of the radiologic features of Hirschsprung disease utilising a unifying stratification of any form of colonic mucosal irregularity on contrast enema. MATERIALS AND METHODS: We conducted a retrospective study of children with suspected Hirschsprung disease managed at a tertiary South African hospital from January 2009 through April 2015. Three observers independently reviewed abdominal radiographs and contrast enemas. The enema analysis included a unifying category of any form of colonic mucosal irregularity. Radiologic features were compared with rectal biopsy results. We used descriptive statistics and the Fisher exact test to compare the radiologic features of children with and without Hirschsprung disease. RESULTS: Ninety-two children with median age of 37 days (range 3 days to 11 years) were included; 50 had biopsy-proven Hirschsprung disease. On enema, any mucosal irregularity, a transition zone and recto-sigmoid ratio inversion were associated with Hirschsprung disease (all P<0.01). Mucosal irregularity showed 96% sensitivity (95% confidence interval [CI] 86.3-99.5) and 71.4% specificity (CI 55.4-84.3); a transition zone showed 86% sensitivity (CI 73.3-94.2) and 90.5% specificity (CI 77.4-97.3); and recto-sigmoid ratio inversion showed 78% sensitivity (CI 64.0-88.5) and 83.3% specificity (CI 68.3-93.0). CONCLUSION: Colonic mucosal irregularity on contrast enema has high sensitivity and moderate specificity for Hirschsprung disease.

Genetic impact on the treatment & management of Hirschsprung disease.

BACKGROUND: The identification of Hirschsprung's disease (HD) as a genetic condition has been a major step forward in understanding the development of the enteric nervous system and conditions arising from ganglion cell maldevelopment. METHOD: A study of the role of genetics in HD was carried out based on previously published findings from more than 400 cases of HD. RESULTS: There are at least 7 pertinent clinical questions related to HD which were further investigated. These included: diagnosis, familial recurrence, long segment and total colonic aganglionosis, syndromic associations, the question of HD-associated enterocolitis, potential causes of postoperative obstructive symptoms after successful surgery, and the apparent low prevalence in premature infants. This review aimed at evaluating the most important concepts of where we have got to in our understanding of where genetic solutions/directions to these clinical problems might lie. Possible genetic reasons for the low prevalence in premature infants was also considered and the possible plasticity of the ENS at that stage as a potential "door of hope" in the future management of HD. CONCLUSION: The study of genetics has made a massive contribution to the understanding and management of HD. It opens a "door of hope" to the future management of the condition. LEVEL OF EVIDENCE: Level V.

Novel Zeb2 gene variation in the Mowat Wilson syndrome (MWS).

BACKGROUND: Mowat Wilson syndrome (MWS) is an uncommon association of Hirschsprung's disease (HSCR). Phenotypic features may develop with time, causing initial difficulties in diagnosis. MWS results from haploinsufficiency of the Zinc finger E-box-binding homeobox 2 (ZEB2) gene, and molecular diagnosis of ZEB2 mutation is required to confirm the diagnosis. We report the first confirmed cases of MWS in three children with the typical facial features, mental retardation, absent corpus callosum, epilepsy, and HSCR and novel Zeb2 variations on DNA analysis. METHODOLOGY: Clinical features were monitored. DNA extracted from peripheral blood was subjected to bidirectional sequencing analysis following PCR DNA amplification. ZEB2 gene results were compared to the ZEB2 reference sequence (ENS00000169554) for variation. Bioinformatic investigation of novel gene variants was via the "Blastx" program function available via the National Center for Biotechnology Information (http://www.bioinfo.org/NPInter/blast/blast_link.cgi). RESULTS: Clinical follow-up showed that the phenotypic features were not all present at birth but developed with time in 2 surviving patients. Several Zeb2 variations were detected in the promoter region of the ZEB2 gene of which 2 were novel (-56A/T 1174 11A/12A). In addition, a novel heterozygous single nucleotide insertion in exon 2 of ZEB2 in one patient results in a frameshift causing deletion of the first 8 amino acids of the ZEB2 protein and an alteration of amino acids 9 (G9A), 11 (R11G), and 12 (C12A). In the third patient, a novel single nucleotide deletion exon 8 (1784delC Het) results in a frameshift at amino acid 595 of translated protein. This shortens protein from 1214 to 594 amino acids and affects the functionality of the critical ZEB2 protein. CONCLUSIONS: MWS is an important link to recognise clinically. It underlines the functionality of the Zeb2 gene in certain syndromic Hirschsprung's disease. These variations probably contribute to the clinical features of the Mowat Wilson phenotype in Hirschsprung's disease but should be confirmed in further research.

Clinical and genetic correlations of familial Hirschsprung's disease.

BACKGROUND: The risk of familial transmission in Hirschsprung's disease (HSCR) currently lacks correlation between the clinical phenotype and the underlying genetic factors. The aim of this study was to clinically evaluate familial HSCR transmission and to correlate with the genetic background. METHODS: Clinical and gene analysis of familial HSCR patients were explored. DNA from 45 patients (35 kindreds) was screened for genetic variations of the RET, and EDNRB genes were screened for genetic variation by semi-automated bi-directional sequencing analysis and matched to controls. MAIN RESULTS: Male:female ratio (3:1) had a female proband in 4 families. Aganglionosis was significantly more frequent with total colonic aganglionosis (TCA) in 40% familial cases (viz: 17/43 (43%) vs. 19/342 non-familial patients (5.6%) (p<0.01)). Transmission of S-HSCR was observed in 13 (31%), which was associated with EDNRB variation. RET gene promoter variation correlated with extended aganglionosis in 6/35 kindreds (17%). In 3 kindreds, both significant EDNRB and RET mutations were identified and where present were associated with increased penetrance in succeeding generations. An increased penetrance with succeeding generations occurred in 6 (14%). In a further 3 generation family, extensive variations in exon 6, 13, and 18 affected 3 males with progressive penetration and aganglionic length, including total intestinal aganglionosis in the further offspring. RET and MEN association was noted in 5 kindreds (14.3%) related to RET variations at Cysteine sites. CONCLUSIONS: Cumulative effects of the RET and EDNRB genes contribute to long-segment and total colonic aganglionosis.

Tissue specific somatic mutations and aganglionosis in Hirschsprung's disease.

BACKGROUND: RET proto-oncogene intron 1 variations [e.g. SNP1 (rs2506004) and SNP2 (rs 2435357)] have been shown to be etiologically important in the pathogenesis of Hirschsprung's disease (HSCR). Although activating somatic RET rearrangements have been identified in certain tumours, this is the first study to confirm somatic gene variation in HSCR. METHODS: DNA was extracted from 53 paraffin embedded tissue samples (HSCR patients n=33, multiple levels n=17), and controls (n=3). Patients were grouped into aganglionic (Group 1), ganglionated (group 2), and transitional (group 3). PCR products of RET intron 1 were screened for genetic variation by semi-automated bi-directional sequencing analysis and matched to unaffected controls from the general population. Comparison was by Fishers exact test. P <0.05 was regarded as significant. RESULTS: HSCR patients included short segment (n=26), long segment colonic [(n=4 (24%)], and total colonic aganglionosis (n=3). RET intronic variations [SNP1 (rs2506004) or SNP2 (rs 2435357)] showed somatic homozygous in affected tissue in 9/12 (75%) Group 1 (aganglionic tissue) compared with 2/5 (40%) and 1/10 (10%) of groups 2 and 3 (P<0.001). Homozygous SNP2 variation was observed in all long segment versus 4/10 short segment. 50% of the short segment cases showing homozygous SNP 1 variation. CONCLUSION: We report somatic mutations in the RET intron 1 region of affected HSCR tissue, confirming for the first time that somatic mutations are present in aganglionic tissue and may promote local aganglionosis through deregulated receptor activity. Detailed understanding of the somatic genetic events that drive congenital aganglionosis may have bearing on diagnosis and therapy.

Associations of anorectal malformations and related syndromes.

Anorectal malformations (ARMs) represent a complex group of congenital anomalies resulting from abnormal development of the hindgut, allantois and Mullerian duct resulting in complete or partial urorectal septal malformations. There is a wide variety of phenotypic expression, ranging from mild anorectal to very complex severe ARM with >75 % having other associated malformations. 50 % of cases are syndromic although many may have other associated anomalies. This suggests a genetic link but the genetics of ARM are highly complex with a number of candidate genes being identified. Many can be classified as "field defects" as a result of a complex set of genetic interactions. Patients with associated malformations can be classified into those with multiple congenital anomalies (non-syndromic), those with chromosomal abnormalities and those with non-chromosomal syndromic associations, also, those with non-chromosomal syndromes and the influence of environmental factors (e.g. drugs in pregnancy). Although much is not known about the aetiology of ARM, the weight of evidence points to genetic factors as major causes for the condition. In this review, we look at the chromosomal and genetic associations and their underlying signalling pathways, to obtain a better understanding of the pathogenetic mechanisms involved in developing ARM. The spectrum of ARM phenotypic expression probably results from involvement and crosstalk between a number of critical signalling systems involved in development of this region. As a result, it may be expressed as a "field developmental defect" with many associated abnormalities. The role of environmental factors in the development of ARM is probably less.

Necrotizing enterocolitis and the placenta - a key etiological link.

AIM: Necrotizing enterocolitis (NEC) is the most common and severe acquired acute neonatal surgical condition, associated with premature neonates. Antenatal factors (e.g. vascular insufficiency and antenatal infections) may be important factors in "priming" the inflammatory cascade, thus predisposing to the disease. This study explores the role of placental pathology in predisposing to NEC pathogenesis. METHODS: 5338 placentas of high risk pregnancies were evaluated for placental insufficiency, infarction, and evidence of antenatal infection. Placentas of 72 premature infants developing surgical NEC (2007-2011) were identified as a separate study group and pathological placental features compared with unaffected infants. RESULTS: Placentas of 72 of the 134 infants with surgically treated NEC (>grade 2 Bells) were available for pathologic evaluation (the remainder having been referred from other delivery units). Placentas of surgical NEC cases had significantly more evidence of noteworthy vascular pathology (placental infarcts) than high risk cases [n=38 (54.5%) versus n=1122 (21%); P<0.01]. Evidence of placental infection/chorioamnionitis or villitis plus evidence of foetal inflammatory response was present in surgical NEC infants versus unaffected infants [n=22 (31.8%) versus n=647 (12%); P<0.01], suggesting a possible pathogenic role. CONCLUSION: This study suggests that exposure to antenatal placental infection may contribute to pathogenesis of NEC by modifying foetal vascular response and warrants further study.

The Hirschsprung's-multiple endocrine neoplasia connection.

The risk of patients with Hirschsprung's disease later developing multiple endocrine neoplasia remains a matter of concern. The multiple endocrine neoplasia 2-Hirschsprung's disease association has been shown to cosegregate in Hirschsprung's disease patients with both short- and long-segment aganglionosis, although patients with long-segment aganglionosis a to carry the greatest risk. The Hirschsprung's disease-medullary thyroid carcinoma relationship also appears to be bi-directional, and activation or suppression of the rearranged during transfection gene appeared to vary over succeeding generations within the same family. Rearranged during transfection gene variations are associated with both conditions. The cosegregation of Hirschsprung's disease and multiple endocrine neoplasia 2 is particularly interesting as it involves both "switch off" and "switch on" of the rearranged during transfection proto-oncogene in the same patient. This cosegregation mostly relates to the cysteine-rich area on RET620 (the "Janus gene"). The mechanism whereby rearranged during transfection influences gene activation in multiple endocrine neoplasia 2 is complex, but genetic variations impair the rearranged during transfection tyrosine kinase response to tyrosine kinase activation, thus appearing to dictate downstream signaling cascade responses. Better understanding of the RET-620 relationship allows for a more cost-effective method of identifying those at risk by focusing rearranged during transfection gene testing to this specific area as a "hot spot". The clinical awareness of possible medullary thyroid carcinoma has led to timely intervention and early treatment of this chemo- and radioresistant tumor with poor prognosis. Establishment of "risk" by genetic testing has become a classic model of molecular medicine being integrated into patient care and offering rearranged during transfection directed prophylactic surgical management. In addition, novel approaches to treatment based on this genetic knowledge have already shown early promise in randomized clinical trials.

The Hirschsprung's-multiple endocrine neoplasia connection

The risk of patients with Hirschsprung's disease later developing multiple endocrine neoplasia remains a matter of concern. The multiple endocrine neoplasia 2-Hirschsprung's disease association has been shown to cosegregate in Hirschsprung's disease patients with both short- and long-segment aganglionosis, although patients with long-segment aganglionosis a to carry the greatest risk. The Hirschsprung's disease-medullary thyroid carcinoma relationship also appears to be bi-directional, and activation or suppression of the rearranged during transfection gene appeared to vary over succeeding generations within the same family. Rearranged during transfection gene variations are associated with both conditions. The cosegregation of Hirschsprung's disease and multiple endocrine neoplasia 2 is particularly interesting as it involves both "switch off" and "switch on" of the rearranged during transfection proto-oncogene in the same patient. This cosegregation mostly relates to the cysteine-rich area on RET620 (the "Janus gene"). The mechanism whereby rearranged during transfection influences gene activation in multiple endocrine neoplasia 2 is complex, but genetic variations impair the rearranged during transfection tyrosine kinase response to tyrosine kinase activation, thus appearing to dictate downstream signaling cascade responses. Better understanding of the RET-620 relationship allows for a more cost-effective method of identifying those at risk by focusing rearranged during transfection gene testing to this specific area as a "hot spot". The clinical awareness of possible medullary thyroid carcinoma has led to timely intervention and early treatment of this chemo- and radioresistant tumor with poor prognosis. Establishment of "risk" by genetic testing has become a classic model of molecular medicine being integrated into patient care and offering rearranged during transfection directed prophylactic surgical management. In addition, novel approaches to treatment based on this genetic knowledge have already shown early promise in randomized clinical trials.

Hirschsprung's disease in the neurologically challenged child.

BACKGROUND: The association between Hirschsprung's disease (HSCR) and central nervous system (CNS) anomalies and syndromes is interesting because of similar developmental pathways. In addition to associated syndromes (e.g., Trisomy 21), these include brain anomalies, mental retardation and growth, ear and hearing deformities, eye hypoplasia, and craniofacial abnormalities, suggesting an neurocristopathy. This group of patients present with neurological challenges and have special challenges in management especially in the older child and adolescent. METHODS: We retrospectively investigated 32 patients with significant HSCR-associated neurological challenges out of a local database of 555 HSCRs (6%). Data were analyzed with details of neurological problem, treatment, complications, and mortality. Long-term outcome was assessed clinically. RESULTS: A total of 32 neurologically challenged children were studied. The male/female ratio was 1.7:1 and all ethnic groups were affected. Abnormalities and syndromes included Down (n = 16) and probable Mowat-Wilson (n = 2) syndromes. Other abnormalities included ophthalmic problems (n = 8), CNS and brain abnormalities (n = 8). Mortality (22%) was mostly related to enterocolitis, particularly in Trisomy 21, ophthalmic problems (n = 8), CNS and brain abnormalities (n = 8). Follow-up age range was 1-34 years (8 years, adolescence and beyond). The outcome was variable, concomitant medical problems were common. Several patients failed to achieve satisfactory continence. CONCLUSION: The association of neurological difficulties in patients with HSCR presents many challenges. Management could involve the exploration and evaluation of alternative treatment choices.

Compound colonic intussusception: a reason for failure of pneumatic reduction.

Intussusception is the most common cause of bowel obstruction in infants older than 3 months. The authors report a case of idiopathic compound (ileocolic/colocolic) intussusception in a 5-month-old girl that was resistant to nonsurgical pneumatic (enema) reduction and necessitated open surgery. Compound intussusception is extremely rare but represents a form of intussusception that is likely to be aggravated by attempts at pneumatic reduction with obvious dangers for the unwary. The literature is reviewed, and the terminology was discussed.

Familial associations in medullary thyroid carcinoma with Hirschsprung disease: the role of the RET-C620 "Janus" genetic variation.

INTRODUCTION: Hirschsprung disease (HSCR) is associated with the later development of multiple endocrine neoplasia (MEN2), because RET gene variations are associated with both conditions. Specifically, HSCR-MEN2 cosegregation mostly relates to the cysteine-rich area at the RET-620 (the "Janus gene"). AIM: The aim of this study was to explore the clinical and genetic associations of HSCR-MEN2 in a cohort of HSCR patients. METHODS: RET gene variation was evaluated by heteroduplex single-strand conformational polymorphism analysis and validated with automated sequencing techniques in HSCR patients (including 18 kindreds). Those with RET C620 variations were subjected to familial evaluation for coexisting HSCR-MEN2. RESULTS: A cohort of 118 patients with HSCR (n = 89) or medullary thyroid carcinoma (n = 29) were studied, including 3 families where a RET-620 point mutation was identified. No C618, C609, or C611 variations were detected. In 1 remarkable 6-generational family (family 3), HSCR in early generations seemed to be later replaced by MEN2A. In the other 2 families with total colonic aganglionosis, a relative with a medullary thyroid carcinoma was identified. CONCLUSION: Gene mutation in the RET-620 position carries significant risk and may be part of a targeted investigation of high-risk areas in HSCR. We propose an alternative hypothesis of endoplasmic reticulum control to explain the changing phenotypic expression.

Total colonic aganglionosis and Hirschsprung's disease: shades of the same or different?

Total colonic aganglionosis is a relatively uncommon form of Hirschsprung's disease (HSCR) occurring in approximately 2-13% of cases. It can probably be divided into total colonic aganglionosis (TCA; defined as aganglionosis extending from the anus to at least the ileocaecal valve, but no more than 50 cm proximal to the ileocaecal valve) and total colonic and small bowel aganglionosis, which may involve a very long segment of aganglionosis. Clinically, they appear to represent a different spectrum of disease in terms of presentation and difficulties in diagnosis which may be experienced, suggesting a different pathophysiology from the more common forms of HSCR. It is not yet clear whether TCA merely represents a long form of HSCR or a different expression of the disease. There are a number of differences between TCA and other forms of HSCR, which require an explanation if its ubiquitous clinical features are to be understood. There is some evidence suggesting that instead of being purely congenital, it may represent certain different pathophysiologic mechanisms, some of which may continue to be active after birth. This study reviews all that is known about the clinical, radiological and histopathologic differences between TCA and the more frequently encountered recto-sigmoid (or short-segment) and correlates them with what is currently known about the genetic and molecular biologic background to find possible pathogenetic mechanisms.

Developmental genes and cancer in children.

Childhood tumours are associated with congenital abnormalities suggesting that disruption of normal developmental processes may be linked with oncogenesis. Genetic and environmental exposures may combine to disrupt critical epigenetic processes during development, thus affecting gene-related signalling pathways and cellular function. This review examines the role of critical genes and processes regulating development such as the polycomb family and sonic hedgehog (SHH) as well as the Wnt signalling pathways and epigenetic variations (Snf5), methylation and loss of heterozygosity in controlling homeotic gene transcription and intracellular chromatin structure. The developmental and perinatal periods appears important as a window of opportunity for cancer research.

The ITGB2 immunomodulatory gene (CD18), enterocolitis, and Hirschsprung's disease.

UNLABELLED: Hirschsprung's disease (HSCR)-associated enterocolitis (HAEC) remains a major contributor to morbidity and mortality associated with HSCR, being sometimes difficult to diagnose in its subclinical form. Its pathogenesis appears to include impaired local defense mechanisms as well as dysfunctional immune response and leukocyte function. In this context, the ITGB2 (CD18) immunomodulation-related gene is a possible candidate in HAEC pathogenesis as it codes for the beta-subunit of leukocyte adhesion molecule lymphocyte function-associated antigen 1, which has an established role in T-cell development and function. ITGB2/CD18 has also been linked to chronic colitis in both human and animal models involving defense mechanisms within colonic mucosa. There is therefore a fairly compelling case for the potential involvement of the ITGB2 (CD18) in HAEC pathogenesis. AIM: The aim of this study was to investigate the ITGB2 immunomodulatory gene (CD18) in a cohort of patients with HSCR and explore its correlation with enterocolitis. PATIENTS AND METHODS: Screening for mutations of the ITGB2 (CD18) gene was performed on DNA extracted from colonic tissue samples and whole blood of 33 HSCR patients controlled by analysis of 60 unaffected individuals from the diverse South African population. Polymerase chain reaction amplification was performed, followed by heteroduplex single-strand conformation polymorphism analysis and bidirectional semiautomated DNA sequencing analysis. RESULTS: Heteroduplex single-strand conformation polymorphism banding patterns of the ITGB2 gene showed variations in 22 HSCR patients (66%), 13 of whom had severe episodes of HAEC, and 6 others had milder symptoms. Of the 13, 6 (46%) had Down's syndrome-associated HSCR. Genetic variations included 1 mutation (D77N), 2 known (V367, V441), and 4 novel polymorphisms (-111T/C, 24G/T, 295G/A, 892A/G). Significant associations were identified in the exon 5' untranslated promotor region (P < .0001), exon 10 (P < .0007), and the 3' untranslated promotor region at 122G/A (P < .0001) and 370 G/T positions (P = .04). Those regions of the gene most frequently associated with HAEC and severe symptoms were those with more than 1 variant identified in the gene. CONCLUSIONS: This study shows that impaired CD18 leukocyte and T regulatory cell regulation can probably be linked to a genetic (ITGB2) predisposition to HAEC. It furthermore provides a possible genetic link to HAEC patient selection, identifying a potential molecular target.

Association of endothelin-beta receptor (EDNRB) gene variants in anorectal malformations.

Animal models have demonstrated the role of genetic influences in anorectal malformations (ARM), although the pathogenetic mechanism remains uncertain. A body of collateral evidence points to possible connection with the endothelin-beta receptor (EDNRB) gene and the endothelin system. This study investigates the EDNRB gene in patients with ARM. Resected surgical specimens of terminal colonic tissue were obtained from 14 children (6 males and 8 females) undergoing surgery for ARM correction with ethical permission. DNA samples were screened for mutations in EDNRB. Polymerase chain reaction amplification of 7 exons of EDNRB was followed by heteroduplex single-strand conformation polymorphism analysis. Heteroduplex single-strand conformation polymorphism variants were validated with automated sequencing techniques on polymerase chain reaction products showing conformational variants in acrylamide gel. All investigated patients with ARM showed mobility shift aberrations and polymorphisms in the EDNRB gene. These included one previously described polymorphism in exon 4 (831G/A) seen in association with Hirschsprung disease and 6 novel polymorphisms identified in exons 1 (178G/A), 2 (552C/T and 561C/T), and 3 (702C/T). No aberrant banding patterns were observed. The exon 1 (178 G/A) variation was identified in 2 (50%) of 4 low lesions compared with 1 (1%) of 84 control samples. The exon 3 (702C/T) single nucleotide polymorphism was present in 3 (60%) of 5 of the supralevator lesions being associated with exon 4 (831G/A). The patient with VATER associations including cardiac and limb anomalies had the 831G/A variation only. Analysis revealed statistically significant differences for the polymorphism 178G/A (P < .01, chi2 with Yates correction = 8.24) compared to controls. Potential disease-related mutations were identified in South African patients with ARM, raising the question of its potential role in the pathogenesis of this condition.

Laparoscopic resection of esophageal stricture with transgastric stapled anastomosis in a child with AIDS.

A tight stricture in the lower esophageal stricture in a child poses significant surgical challenges. We report the first case of a laparoscopically assisted resection of a distal esophageal stricture in a 2-year-old girl with clinical AIDS (CDC stage 3). The patient presented with dysphagia, vomiting, and progressive weight loss. A barium swallow confirmed a distal tight esophageal stricture in the lower esophagus. After the second dilatation attempt failed a gastrostomy was inserted and highly active antiretroviral therapy treatment commenced. Follow-up contrast studies showed a nearly complete obstruction of the distal esophagus. A laparoscopically assisted resection of the esophageal stricture with a primary stapled anastomosis was performed with good results. At follow-up 8 months postoperative the child was tolerating feeds well and thriving.

Abnormal constitutional karyotypes in patients with neuroblastoma: a report of four new cases and review of 47 others in the literature.

Anomalies of constitutional karyotype, which have led to the discovery of oncogenes and tumor-suppressor genes in embryonal tumors such as retinoblastoma and Wilms tumor, have, until recently, rarely been reported until recently in neuroblastoma. We present four new cases of neuroblastoma associated with (a) a mosaicism for monosomy 22; (b) an 11q interstitial deletion; (c) a pericentric inversion of chromosome 9 at band 9p21; and (d) a Robertsonian translocation t(13;14). These anomalies and 47 others in the literature are worthy of interest, because some are recurrent, involving the same chromosome regions (1p36, 2p23, 3q, 11q23, and 15q), and some anomalies are situated on chromosome regions known to contain genes involved in neuroblastoma development (1p, 2p, 9p, 11q, 16q, and 17q). Chromosome regions 3q and 15q, observed several times, may also contain genes significant for neuroblastoma onset or development. Furthermore, the lack of neuroblastoma in patients with Down syndrome and Klinefelter or triple-X syndromes, together with a probable excess of neuroblastoma in patients with Turner syndrome, suggests that genes of importance for neuroblastoma may map to chromosomes X and 21. A search for genes implicated in neuroblastoma biology should use these data.