Three-Dimensional Imaging of the Enteric Nervous System in Human Pediatric Colon Reveals New Features of Hirschsprung's Disease.

BACKGROUND & AIMS: Hirschsprung's disease is defined by the absence of the enteric nervous system (ENS) from the distal bowel. Primary treatment is "pull-through" surgery to remove bowel that lacks ENS, with reanastomosis of "normal" bowel near the anal verge. Problems after pull-through are common, and some may be due to retained hypoganglionic bowel (ie, low ENS density). Testing this hypothesis has been difficult because counting enteric neurons in tissue sections is unreliable, even for experts. Tissue clearing and 3-dimensional imaging provide better data about ENS structure than sectioning. METHODS: Regions from 11 human colons and 1 ileal specimen resected during Hirschsprung's disease pull-through surgery were cleared, stained with antibodies to visualize the ENS, and imaged by confocal microscopy. Control distal colon from people with no known bowel problems were similarly cleared, stained, and imaged. RESULTS: Quantitative analyses of human colon, ranging from 3 days to 60 years old, suggest age-dependent changes in the myenteric plexus area, ENS ganglion area, percentage of myenteric plexus occupied by ganglia, neurons/mm2, and neuron Feret's diameter. Neuron counting using 3-dimensional images was highly reproducible. High ENS density in neonatal colon allowed reliable neuron counts using 500-µm2 × 500-µm2 regions (36-fold smaller than in adults). Hirschsprung's samples varied 8-fold in proximal margin enteric neuron density and had diverse ENS architecture in resected bowel. CONCLUSIONS: Tissue clearing and 3-dimensional imaging provide more reliable information about ENS structure than tissue sections. ENS structure changes during childhood. Three-dimensional ENS anatomy may provide new insight into human bowel motility disorders, including Hirschsprung's disease.

Assessing fecal load with ultrasound in children with colorectal pathology: ReKiSo study.

PURPOSE: To evaluate bowel management for children with colorectal pathology by measuring transverse rectal diameter (TRD) and assessing fecal load with transabdominal rectal ultrasound (TRU). METHODS: Prospective case-control study of children receiving bowel management (BM) between 04/2023 and 04/2024 was done. There was inclusion of patients with Hirschsprung disease (HD), anorectal malformation (ARM) and functional constipation (FC). Patients with other congenital or neurological conditions were excluded. Control group consisted of inpatients and outpatients without abdominal complaints. FC was diagnosed according to ROM-IV-criteria. For HD and ARM, we followed a list of symptoms. To assess fecal load, we visualized the TRD using the Klijn (Klijn et al. in J Urol 172:1986-1988, 2004) method. The bladder was moderately full. The fecal load was assessed retrograde from the rectum. Follow-up was at 1/3/6 months. Secondary data were collected from medical records. Sample size calculated a priori and follow-up group with new gathered data. RESULTS: p value for TRD in all groups significant with p < 0.05 and in grouped follow-up. CONCLUSION: Ultrasound is a useful tool for assessing fecal load and helps diagnose constipation and monitor BM. Irrespective of colorectal pathology, a cut-off of 3 cm seems to discriminate between children without constipation/overload symptoms and asymptomatic patients. We present a radiation-free method for monitoring bowel management.

Congenital segmental dilatation of the colon in a newborn: a radiologic perspective of an unusual entity.

A newborn with congenital segmental dilatation of the intestine affecting the colon is presented. This rare condition, unrelated to Hirschsprung's disease, may affect any portion of the bowel and is characterized by focal dilatation of a segment of bowel flanked by normal proximal and distal bowel. While reported in the surgical literature, congenital segmental dilatation of the intestine has not been reported in the pediatric radiology literature even though pediatric radiologists may be the first to encounter imaging suggesting the diagnosis. We therefore present the characteristic imaging findings, including abdominal radiographs and images from a contrast enema, and discuss the clinical presentation, pathology findings, associations, treatment, and prognosis of congenital segmental dilatation of the intestine to increase awareness of this unusual diagnosis.

Diagnosis of Hirschsprung disease by hydrocolonic sonography in children.

OBJECTIVES: To compare hydrocolonic sonography with histopathology for diagnosing children with symptoms highly suggestive of Hirschsprung disease (HD). METHODS: In this prospective study, patients presenting refractory constipation highly suggestive of HD underwent hydrocolonic sonography with retrograde infusion of saline into the colon. The dilated segments, narrowed segments, luminal diameter ratio, transition zone (TZ), thickening, and blood perfusion of the upstream bowel were evaluated. The sensitivity and specificity of combined and single parameters were determined in comparison with biopsy. RESULTS: One hundred and three children were included in this study; 49 were confirmed to have HD. The luminal diameter ratio showed superiority over other parameters. An area under the curve (AUC) of 0.969 (95% confidence interval [CI]: 0.936-1.000) and a cutoff value of 1.51 were established by receiver operating characteristic (ROC) curve analysis of the luminal diameter ratio (sensitivity: 89.8%; specificity: 96.3%). By combining the luminal diameter ratio as the major criterion with two minor criteria, hydrocolonic sonography showed the same sensitivity (91.8%) and better specificity (96.3% vs 87%) than contrast enema, but this difference was not statistically significant (p = 0.063). Consistency analysis showed a kappa value of 0.825 (p < 0.001), indicating excellent agreement between hydrocolonic sonography and contrast enema. CONCLUSIONS: Hydrocolonic sonography is a valuable diagnostic tool with both high sensitivity and specificity for HD diagnosis, allowing morphological and vascular assessments of the colon, and correlates well with contrast enema. In the appropriate setting, hydrocolonic sonography may be an alternative screening method for HD in a large group of children with constipation. Key Points • Hydrocolonic sonography is a simple, well-tolerated diagnostic tool with both high sensitivity and specificity for HD diagnosis. • Hydrocolonic sonography allows morphological and vascular assessments of the colon, and correlates well with contrast enema. • Hydrocolonic sonography is a possible alternative modality for paediatric patients highly suggestive of HD.

Sonographic findings of total colonic aganglionosis in a neonate with Haddad syndrome: A case report.

Haddad syndrome is a rare congenital disorder characterized by congenital central hypoventilation syndrome and Hirschsprung disease. Total colonic aganglionosis is a rare and long-segment form of Hirschsprung disease, which is primarily diagnosed using contrast enemas. However, the diagnostic performance of contrast enemas is relatively low, making the diagnosis of total colonic aganglionosis challenging. In neonates, ultrasound may be used as an additional imaging modality for the diagnosis of Hirschsprung disease. We describe the unique sonographic findings of total colonic aganglionosis in a term neonate with failure to pass meconium and respiratory distress, who was subsequently diagnosed with Haddad syndrome.

[HIRSCHSPRUNG'S DISEASE IN TEENAGERS].

Aim - based on the clincal experience of monitoring and treatment of teenagers with Hirschsprung's disease (HD), to study clinical aspects of the disease in older children and to establish an adequate diagnostic and treatment policy. The paper is based on the analysis of the results of examination and treatment of 26 children with Hirschsprung's disease, who were first diagnosed with the disease at the age of 10 years and older. There were 19 (73.08%) boys and 7 (26.92%) girls. The following diagnostic methods were used: X-ray examination of the large intestine, ultrasonography of the abdominal organs and the large intestine, rectosigmoidoscopy, morphological examination of biopsy material, immunohistological examination for acetylcholinesterase (AChE). Nonparametric statistical methods were used due to the small sample and the prevalence of the analysis of qualitative rather than quantitative criteria. Hirschsprung's disease in older children has a latent course with long periods of functional compensation. The rectal form of pathology predominates (57.69%). The main diagnostic methods are anamnesis, features of the clinical course of the pathology, irrigoscopy, morphological examination of full-thickness rectal biopsies and immunohistochemical examination of the rectal mucosa for AChE. 84,62% of teenagers underwent one-stage surgery without postoperative complications; 15,38% of patients had indications for colostomy.

Pulmonary Follow-Up Imaging in Cartilage-Hair Hypoplasia: a Prospective Cohort Study.

Cartilage-hair hypoplasia is a syndromic immunodeficiency with short stature, chondrodysplasia, and variable degree of immune dysfunction. Patients with cartilage-hair hypoplasia are prone to recurrent respiratory tract infections, and the prevalence of bronchiectasis ranges from 29 to 52%. Pulmonary complications contribute significantly to the mortality; therefore, regular lung imaging is essential. However, the optimal schedule for repeated lung imaging remains unestablished. We determined the rate and correlates of progression of structural lung changes in a prospectively followed cohort of 16 patients with cartilage-hair hypoplasia. We analyzed clinical, laboratory, and pulmonary functional testing data and performed lung magnetic resonance imaging at a median interval of 6.8 years since previous imaging. Imaging findings remained identical or improved due to disappearance of inflammatory changes in all evaluated patients. Patients with subtle signs of bronchiectasis on imaging tended to have low immunoglobulin M levels, as well as suffered from pneumonia during the follow-up. In conclusion, our results suggest slow if any development of bronchiectasis in selected subjects with cartilage-hair hypoplasia.

Brain size reductions associated with endothelin B receptor mutation, a cause of Hirschsprung's disease.

BACKGROUND: ETB has been reported to regulate neurogenesis and vasoregulation in foetal development. Its dysfunction was known to cause HSCR, an aganglionic colonic disorder with syndromic forms reported to associate with both small heads and developmental delay. We therefore asked, "is CNS maldevelopment a more general feature of ETB mutation?" To investigate, we reviewed the micro-CT scans of an ETB-/- model animal, sl/sl rat, and quantitatively evaluated the structural changes of its brain constituents. METHODS: Eleven neonatal rats generated from ETB+/- cross breeding were sacrificed. Micro-CT scans were completed following 1.5% iodine-staining protocols. All scans were reviewed for morphological changes. Selected organs were segmented semi-automatically post-NLM filtering: TBr, T-CC, T-CP, OB, Med, Cer, Pit, and S&I Col. Volumetric measurements were made using Drishti rendering software. Rat genotyping was completed following analysis. Statistical comparisons on organ volume, organ growth rate, and organ volume/bodyweight ratios were made between sl/sl and the control groups based on autosomal recessive inheritance. One-way ANOVA was also performed to evaluate potential dose-dependent effect. RESULTS: sl/sl rat has 16.32% lower body weight with 3.53% lower growth rate than the control group. Gross intracranial morphology was preserved in sl/sl rats. However, significant volumetric reduction of 20.33% was detected in TBr; similar reductions were extended to the measurements of T-CC, T-CP, OB, Med, and Pit. Consistently, lower brain and selected constituent growth rates were detected in sl/sl rat, ranging from 6.21% to 11.51% reduction. Lower organ volume/bodyweight ratio was detected in sl/sl rats, reflecting disproportional neural changes with respect to body size. No consistent linear relationships exist between ETB copies and intracranial organ size or growth rates. CONCLUSION: Although ETB-/- mutant has a normal CNS morphology, significant size reductions in brain and constituents were detected. These structural changes likely arise from a combination of factors secondary to dysfunctional ET-1/ET-3/ETB signalling, including global growth impairment from HSCR-induced malnutrition and dysregulations in the neurogenesis, angiogenesis, and cerebral vascular control. These changes have important clinical implications, such as autonomic dysfunction or intellectual delay. Although further human study is warranted, our study suggested comprehensive managements are required for HSCR patients, at least in ETB-/- subtype.

Visualization of the human enteric nervous system by probe confocal laser endomicroscopy: a first real-time observation of Hirschsprung's disease and allied disorders.

BACKGROUND: Our group previously proved that the human enteric nervous system can be visualized with confocal laser endomicroscopy after topical application of cresyl violet using surgically resected intestine specimens. The present report documents the first in vivo visualization of the human enteric nervous system with confocal laser endomicroscopy using local cresyl violet staining. The aim of this study was to evaluate the technical feasibility and clinical efficiency of confocal laser endomicroscopy in patients with Hirschsprung's disease and allied disorders in vivo. METHODS: Confocal laser endomicroscopy was performed in vivo in two patients to confirm the presence of the enteric nervous system during surgery in patients with Hirschsprung's disease and allied disorders. Cresyl violet was gently injected from the serosal side into the muscular layer of the intestine, and scanning was performed within 30 min. Then, the scanned intestines were resected, and the visualized area of the specimens was pathologically evaluated. RESULTS: The ganglion cell nuclei and the enteric nervous system network were clearly visualized intraoperatively in both cases. The morphological findings were similar to the pathological findings of the enteric nervous system in both cases although the period of visibility was brief. CONCLUSION: This study demonstrated the first, real-time observation of the enteric nervous system in humans using confocal laser endomicroscopy and suggest the potential to identify the enteric nervous system intra-operatively during surgery for Hirschsprung's disease and allied disorders.

Surgery, Surgical Pathology, and Postoperative Management of Patients With Hirschsprung Disease.

Endorectal pullthrough surgery is integral in the treatment of patients with Hirschsprung disease. Several different surgical procedures exist, which share as common goals to excise the aganglionic segment and upstream transition zone and attach ganglionic bowel just proximal to the anal canal. The operation requires collaboration between surgeon and pathologist to localize ganglionic bowel and prevent retention of transition zone. Intraoperative frozen sections are extremely important, first to establish that ganglion cells are present and subsequently to exclude features of transition zone (partial circumferential aganglionosis, myenteric hypoganglionosis, and submucosal nerve hypertrophy) at the proximal surgical (anastomotic) margin. Postoperative histopathological analysis of resection specimens should be tailored to document distal aganglionosis, document the length of the aganglionic segment and its proximity to the anastomotic margin, and confirm that transition zone has been resected completely. Adherence to the recommendations described in this review will reduce the likelihood of transition zone pullthrough and should decrease the incidence of persistent postoperative obstructive symptoms.

Barium enema findings in total colonic aganglionosis: a single-center, retrospective study.

BACKGROUND: Preoperative diagnosis of total colonic aganglionosis is important for the rational choice of treatment. The present study aimed to evaluate the diagnostic performance of radiographic signs on preoperative barium enema in patients with total colonic aganglionosis. METHODS: Forty-four patients [41 (3-659) days] with total colonic aganglionosis, including 17 neonatal patients, who received preoperative barium enema at Beijing Children's Hospital, from January 2007 to December 2019 were included. All radiographs were retrospectively restudied by 2 pediatric radiologists to ascertain radiographic signs including rectosigmoid index, transition zone, irregular contraction, gas-filled small bowel, microcolon, question-mark-shaped colon and ileocecal valve reflux. Kappa test was performed to assess the accuracy and consistency of the radiographic signs. RESULTS: The 2 radiologists showed slight agreement for gas-filled small bowel, microcolon and rectosigmoid index, fair agreement for transition zone and irregular contraction, and moderate agreement for question-mark-shaped colon and ileocecal valve reflux (Kappa values, 0.043, 0.075, 0.103, 0.244, 0.397, 0.458 and 0.545, respectively). In neonatal patients, the 2 radiologists showed moderate agreement for ileocecal valve reflux and substantial agreement for question-mark-shaped colon (Kappa values, 0.469 and 0.667, respectively). In non-neonatal patients, the 2 radiologists showed substantial agreement for ileocecal valve reflux (Kappa value, 0.628). In 36 patients with total colonic aganglionosis extending to the ileum, the accuracies of question-mark-shaped colon, ileocecal valve reflux and the combination of both were 47%, 53%, and 75%, respectively, in one radiologist and 53%, 50% and 72%, respectively, in the other radiologist. CONCLUSIONS: Ileocecal valve reflux is a relatively reliable radiographic sign for diagnosing total colonic aganglionosis and could improve the diagnostic accuracy upon combination with question-mark-shaped colon.

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.

Comparison of Barium Enema and frozen section results in the diagnosis of Hirschsprung's Disease in a tertiary care hospital at Aceh, Indonesia.

INTRODUCTION: Hirschsprung's Disease (HD) also called congenital aganglionic megacolon is a disorder caused by undeveloped distal to proximal intestinal nerve ganglion cells. Diagnosis includes determining the aganglionic segment through barium enema radiology examination and histopathology of frozen section with permanent section as gold standard. Determining the diagnostic value of this modality is important for operative management decision. MATERIALS AND METHODS: The study was a retrospective, cross-sectional study with diagnostic test design. Patient data were obtained in the form of clinical symptoms, barium enema, and frozen section expertise were assessed for the suitability of the diagnostic value by referring to the permanent section as the gold standard. RESULT: Thirty-four patient data were obtained. The sensitivity, specificity, and accuracy of barium enemas were 95%, 69.2%, and 82%, respectively. The values of sensitivity, specificity, and accuracy of frozen section were 95%, 92.8%, and 88%, respectively. The Cohen-Kappa statistic value was 0.62 (good agreement). CONCLUSION: Accuracy of FS is better than barium enema in diagnosing HD. In health care center with limitation of histopathological facility, BE could be used as the alternative procedure as interrater comparisons showed good agreement. Therefore, either frozen section or barium enema can be carried out in common or in separate term.

Digital pathology imaging and computer-aided diagnostics as a novel tool for standardization of evaluation of aganglionic megacolon (Hirschsprung disease) histopathology.

Based on a recently introduced immunohistochemical panel (Bachmann et al. 2015) for aganglionic megacolon (AM), also known as Hirschsprung disease, histopathological diagnosis, we evaluated whether the use of digital pathology and 'machine learning' could help to obtain a reliable diagnosis. Slides were obtained from 31 specimens of 27 patients immunohistochemically stained for MAP2, calretinin, S100ß and GLUT1. Slides were digitized by whole slide scanning. We used a Definiens Developer Tissue Studios as software for analysis. We configured necessary parameters in combination with 'machine learning' to identify pathological aberrations. A significant difference between AM- and non-AM-affected tissues was found for calretinin (AM 0.55% vs. non-AM 1.44%) and MAP2 (AM 0.004% vs. non-AM 0.07%) staining measurements and software-based evaluations. In contrast, S100ß and GLUT1 staining measurements and software-based evaluations showed no significant differences between AM- and non-AM-affected tissues. However, no difference was found in comparison of suction biopsies with resections. Applying machine learning via an ensemble voting classifier, we achieved an accuracy of 87.5% on the test set. Automated diagnosis of AM by applying digital pathology on immunohistochemical panels was successful for calretinin and MAP2, whereas S100ß and GLUT1 were not effective in diagnosis. Our method suggests that software-based approaches are capable of diagnosing AM. Our future challenge will be the improvement of efficiency by reduction of the time-consuming need for large pre-labelled training data. With increasing technical improvement, especially in unsupervised training procedures, this method could be helpful in the future.

Neurocristopathies: Enigmatic Appearances of Neural Crest Cell-derived Abnormalities.

The neural crest is an important transient structure that develops during embryogenesis in vertebrates. Neural crest cells are multipotent progenitor cells that migrate and develop into a diverse range of cells and tissues throughout the body. Although neural crest cells originate from the ectoderm, they can differentiate into mesodermal-type or endodermal-type cells and tissues. Some of these tissues include the peripheral, autonomic, and enteric nervous systems; chromaffin cells of the adrenal medulla; smooth muscles of the intracranial blood vessels; melanocytes of the skin; cartilage and bones of the face; and parafollicular cells of the thyroid gland. Neurocristopathies are a group of diseases caused by the abnormal generation, migration, or differentiation of neural crest cells. They often involve multiple organ systems in a single person, are often familial, and can be associated with the development of neoplasms. As understanding of the neural crest has advanced, many seemingly disparate diseases, such Treacher Collins syndrome, 22q11.2 deletion syndrome, Hirschsprung disease, neuroblastoma, neurocutaneous melanocytosis, and neurofibromatosis, have come to be recognized as neurocristopathies. Neurocristopathies can be divided into three main categories: dysgenetic malformations, neoplasms, and combined dysgenetic and neoplastic syndromes. In this article, neural crest development, as well as several associated dysgenetic, neoplastic, and combined neurocristopathies, are reviewed. Neurocristopathies often have clinical manifestations in multiple organ systems, and radiologists are positioned to have significant roles in the initial diagnosis of these disorders, evaluation of subclinical associated lesions, creation of treatment plans, and patient follow-up. Online supplemental material is available for this article. ©RSNA, 2019.

Optimal time for single-stage pull-through colectomy in infants with short-segment Hirschsprung disease.

OBJECTIVE: Short-segment Hirschsprung disease (HSCR) is the predominant type of HSCR that affects approximately 75% of patients. Whether single-stage endorectal pull-through (ERPT) surgery is appropriate for neonatal patients with HSCR has not been definitively determined. This retrospective cohort study concerning infants with short-segment HSCR investigated the optimal age for single-stage ERPT surgery, regardless of the operative approach. METHODS: The 198 patients were stratified by operative age ≤ 3 or > 3 months (groups A or B, respectively, n = 62 and 136, respectively). Diagnoses of short-segment HSCR were conducted by preoperative contrast enema and rectal suction biopsy with acetylcholinesterase immunohistochemical staining. The perioperative clinical course for all patients was reviewed and the accuracy rate of the preoperative diagnoses and postoperative short- and midterm outcomes were assessed. RESULTS: The rates of diagnostic accuracy, according to the results of the preoperative contrast enema or rectal suction biopsy, were lower in group A (67.2 and 93.5%, respectively) than in group B (81.4 and 94.9%, respectively). In groups A and B, 49 (79.1%) and 108 (79.4%) infants, respectively, completed follow-up examinations. The short-term outcomes were postoperative HSCR-associated enterocolitis, adhesive bowel obstruction, anastomosis leakage, and anal stenosis during the first 12 months after surgery. The midterm outcomes were incontinence and constipation at ~24 months after surgery. Compared with group B, group A experienced more incidences of anastomotic leakage in the short-term and more soiling in the midterm. In groups A and B, the rates of constipation recurrence were nil and 1.9%, respectively. CONCLUSION: Infants with HSCR ≤3 months old at the time of single-stage ERPT surgery showed lower rates of accurate and conclusive diagnostic results and poorer postoperative outcomes. Waiting to perform this surgery until infants are older might be more beneficial.

Barium Enema Revisited in the Workup for the Diagnosis of Hirschsprung's Disease.

OBJECTIVE: To analyse the diagnostic capacity of barium enema (BE) in the diagnostic investigation for Hirschsprung's disease (HD) was analyzed for transition zone (TZ) identification and rectosigmoid index (RSI) ≤1.0 determination. PATIENTS AND METHODS: BE images were analyzed retrospectively by 2 examiners and the results were compared with the histopathology of rectal biopsies. RESULTS: TZ identification and RSI ≤1.0 were assessed separately and combined in 43 patients. Twelve (27.9%) patients had the diagnosis of HD based on rectal biopsies. TZ identification presented better diagnostic capacity for the 2 examiners than RSI ≤1.0. However, interexaminer agreement was higher for RSI ≤1.0 than for TZ identification. The combination of TZ identification and RSI ≤1.0 increased the sensitivity (83.3%-92.3%) and the negative predictive value (90.4%-92.3%). CONCLUSION: Therefore, the high diagnostic sensitivity of TZ identification combined to RSI ≤1.0 reinforces the usefulness of these BE parameters in the screening for Hirschsprung's disease.

Neuroimaging findings in Mowat-Wilson syndrome: a study of 54 patients.

PURPOSE: Mowat-Wilson syndrome (MWS) is a genetic disease characterized by distinctive facial features, moderate to severe intellectual disability, and congenital malformations, including Hirschsprung disease, genital and eye anomalies, and congenital heart defects, caused by haploinsufficiency of the ZEB2 gene. To date, no characteristic pattern of brain dysmorphology in MWS has been defined. METHODS: Through brain magnetic resonance imaging (MRI) analysis, we delineated a neuroimaging phenotype in 54 MWS patients with a proven ZEB2 defect, compared it with the features identified in a thorough review of published cases, and evaluated genotype-phenotype correlations. RESULTS: Ninety-six percent of patients had abnormal MRI results. The most common features were anomalies of corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), and white matter abnormalities (reduction of thickness 40.7%, localized signal alterations 22.2%). Other consistent findings were large basal ganglia, cortical, and cerebellar malformations. Most features were underrepresented in the literature. We also found ZEB2 variations leading to synthesis of a defective protein to be favorable for psychomotor development and some epilepsy features but also associated with corpus callosum agenesis. CONCLUSION: This study delineated the spectrum of brain anomalies in MWS and provided new insights into the role of ZEB2 in neurodevelopment.Genet Med advance online publication 10 November 2016.

Cartilage-hair hypoplasia with normal height in childhood-4 patients with a unique genotype.

The manifestations of cartilage-hair hypoplasia (CHH), a metaphyseal chondrodysplasia caused by RMRP mutations, include short stature, hypoplastic hair, immunodeficiency and increased risk of malignancies. Clinical features show significant variability. We report a patient with normal height until age 12.5 years (-1.6 SDS at 11 years) who was diagnosed with CHH at 14 years. RMRP sequencing revealed compound heterozygosity for g.70A>G mutation and a 10-nucleotide duplication at position -13 (TACTCTGTGA). Through the Finnish Skeletal Dysplasia Register, we identified 3 additional patients with identical genotype. Two of them also showed unusually mild growth failure (height SDS -1.6 at 14 years and -3.0 at 12 years, respectively). Three of the 4 patients suffered from recurrent infections; 1 developed progressive bronchiectasis and another died from aggressive lymphoma. Our findings expand the phenotypic variability in CHH to include normal childhood height. The milder growth retardation related to this particular genotype was not associated with less severe extra-skeletal manifestations, emphasizing the need for careful follow-up also in CHH patients with mild-skeletal manifestations.