Post-traumatic stress as a determinant of quality of life in pediatric solid-organ transplant recipients.

Living with end-stage organ failure is associated with an accumulation of traumatic medical events, and despite recovery after solid-organ transplantation (SOT), many children continue to exhibit lower quality of life (QOL). Few studies have examined the relationship between post-traumatic stress disorder (PTSD) and QOL among pediatric SOT recipients. We conducted a retrospective, cross-sectional review of 61 pediatric SOT recipients (12 heart, 30 kidney, and 19 liver) to evaluate the association of PTSD with self-reported QOL. PTSD was measured by the Child Trauma Screening Questionnaire (CTSQ), and QOL was measured using the PedsQL and PedsQL Transplant Module (PedsQL-TM) surveys. Demographics, baseline, and contemporaneous factors were tested for independent association. SOT recipients were 15.2 (12.1-17.6) years old at survey completion. Median CTSQ score was 2 (1-3), highest in kidney recipients, and 13% were identified as high risk for PTSD. Median PedsQL score was 83 (70-91) and significantly associated with the CTSQ score (r = -.68, p < .001). Median PedsQL Transplant Module score was 89 (83-95) and similarly associated with the CTSQ score (r = -.64, p < .001). Age at time of surveys and presence of any disability were also independently associated with PedsQL and PedsQL-TM, respectively. When adjusted for Emotional Functioning, CTSQ remained associated with PedsQL subscores (r = -.65, p < .001). Trauma symptoms are a major modifiable risk factor for lower self-perceived QOL and represent a potentially important target for post-transplant rehabilitation. Additional research is needed to understand the root contributors to PTSD and potential treatments in this population.

Self-reported physical activity and lack of association with health-related quality of life in a pediatric solid-organ transplant population.

BACKGROUND: Physical activity (PA) has been shown to have benefits, including improving health-related quality of life (HRQOL). However, there are few and conflicting studies assessing PA and its relationship with HRQOL in a pediatric solid-organ transplant (SOT) population. The aim of this study was to assess whether overall HRQOL was associated with PA and to determine whether that association was independent of other baseline and contemporaneous clinical and demographic indicators. METHODS: A retrospective cross-sectional review was performed on 55 pediatric transplant patients (13 heart, 27 kidney, and 15 liver transplant). PA was measured by PAQ-C/PAQ-A, and HRQOL was measured using PedsQL. Demographics, baseline, and contemporaneous data were collected. RESULTS: There were no significant differences in baseline and contemporaneous characteristics between heart, kidney, and liver transplant recipients. SOT recipients were 15.0 (11.0-18.0) years old at completion of surveys. Median PAQ score was 2.3 (1.6-3.2), PedsQL total score was 77 (65-91), and PedsQL physical functioning score was 88 (72-97). The PedsQL total score was not significantly associated with PAQ score. The PAQ score was significantly associated with physical functioning subscore of the PedsQL (r = 0.37, p < 0.01). Higher physical functioning score was associated with time since transplant (r = 0.29, p = 0.031). CONCLUSION: Our SOT cohort has a HRQOL similar to other chronic conditions and higher than previous reported HRQOL in pediatric SOT populations. Higher levels of PA and longer time since transplant are associated with higher physical functioning scores.

Sequential paternal haploidentical donor liver and HSCT in EPP allow discontinuation of immunosuppression post-organ transplant.

BACKGROUND: EPP is characterized by photosensitivity and by liver disease. When LT is performed in EPP, recurrence often occurs in the allograft due to ongoing protoporphyrin production in bone marrow. Therefore, curative treatment requires allogeneic HSCT after LT. Long-term immunosuppression could be spared by using the same donor for both transplants. METHODS: A 2-year-old girl with EPP in liver failure underwent liver transplant from her father. Transfusion and apheresis therapy were used to lower protoporphyrin levels before and after liver transplant. Ten weeks after liver transplant, she underwent HSCT, using the same donor. Conditioning was with treosulfan, fludarabine, cyclophosphamide, and ATG. GVHD prophylaxis was with abatacept, methotrexate, MMF, and tacrolimus. We followed the patient's erythrocyte protoporphyrin and liver and skin health for 2 years after transplant. RESULTS: After hematopoietic stem cell engraftment, a decline in protoporphyrin levels was observed, with clinical resolution of photosensitivity. Liver biopsies showed no evidence of EPP. Mild ACR occurred and responded to steroid pulse. Two years post-HSCT, the patient has been weaned off all immunosuppression and remains GVHD and liver rejection free. CONCLUSIONS: Sequential liver and HSCT from the same haploidentical donor are feasible in EPP. This strategy can allow for discontinuation of immune suppression.

The effects of child anxiety and depression on concordance between parent-proxy and self-reported health-related quality of life for pediatric liver transplant patients.

BACKGROUND: HRQOL is a key outcome following pediatric LT. Parent-proxy reports may substitute for patients unable to report their own HRQOL. This study compared parent-proxy and self-reported HRQOL in children who have undergone LT. METHODS: Pediatric LT recipients between the ages of 8 and 18 years, and a parent, completed self and proxy versions of the PeLTQL questionnaire, PedsQL Generic and Transplant modules, and standardized measures of depression and anxiety. RESULTS: Data from 129 parent-patient dyads were included. Median parent age was 44 years, and most (89%) were mothers. Median patient age was 2.5 years at LT and 13.6 years at the time of study participation. Parents had significantly lower scores than patients on PedsQL total generic (70.8 ± 18.5 and 74.3 ± 19.0, p = .01), PeLTQL coping and adjustment (63.0 ± 15.6 and 67.3 ± 16.2, p < .01), and social-emotional (66.3 ± 14.9 and 71.9 ± 15.6, p < .001) domains. Higher patient anxiety and depression were related to larger absolute differences between parent-proxy and self-reported scores on all HRQOL measures (all p < .05). In this disparity, parents reported higher HRQOL scores than their child as self-reported anxiety and depression scores increased. CONCLUSIONS: Differences in concordance between parent-proxy and self-reported HRQOL scores can be more prominent when children have more symptoms of anxiety and depression. Children's mental health symptoms should be queried, if feasible, when interpreting differences in parent and child reports of HRQOL.

Idiopathic splenomegaly in childhood and the spectrum of RAS-associated lymphoproliferative disease: a case report.

BACKGROUND: KRAS (KRAS proto-oncogene, GTPase; OMIM: 190,070) encodes one of three small guanosine triphosphatase proteins belonging to the RAS family. This group of proteins is responsible for cell proliferation, differentiation and inhibition of apoptosis. Gain-of-function variants in KRAS are commonly found in human cancers. Non-malignant somatic KRAS variants underlie a subset of RAS-associated autoimmune leukoproliferative disorders (RALD). RALD is characterized by splenomegaly, persistent monocytosis, hypergammaglobulinemia and cytopenia, but can also include autoimmune features and lymphadenopathy. In this report, we describe a non-malignant somatic variant in KRAS with prominent clinical features of massive splenomegaly, thrombocytopenia and lymphopenia. CASE PRESENTATION: A now-11-year-old girl presented in early childhood with easy bruising and bleeding, but had an otherwise unremarkable medical history. After consulting for the first time at 5 years of age, she was discovered to have massive splenomegaly. Clinical follow-up revealed thrombocytopenia, lymphopenia and increased polyclonal immunoglobulins and C-reactive protein. The patient had an unremarkable bone marrow biopsy, flow cytometry showed no indication of expanded double negative T-cells, while malignancy and storage disorders were also excluded. When the patient was 8 years old, whole exome sequencing performed on DNA derived from whole blood revealed a heterozygous gain-of-function variant in KRAS (NM_004985.5:c.37G > T; (p.G13C)). The variant was absent from DNA derived from a buccal swab and was thus determined to be somatic. CONCLUSIONS: This case of idiopathic splenomegaly in childhood due to a somatic variant in KRAS expands our understanding of the clinical spectrum of RAS-associated autoimmune leukoproliferative disorder and emphasizes the value of securing a molecular diagnosis in children with unusual early-onset presentations with a suspected monogenic origin.

Physical activity and its correlates in a pediatric solid-organ transplant population.

PA has been shown to have benefits in SOT patients. Studies assessing physical activity levels and its correlates in a pediatric solid-organ transplant population are limited. The aim of this study was to assess PA levels and identify baseline and contemporaneous factors that contribute to PA in a pediatric SOT population. A retrospective cross-sectional review was performed on 58 pediatric transplant patients (16 heart, 29 kidney, and 13 liver transplant). PA was measured by PAQ-C or PAQ-A. Demographics, baseline, and contemporaneous factors were collected. There were no significant differences in baseline and contemporaneous characteristics between heart, kidney, and liver transplant recipients. SOT recipients were 15.2 [12.3-17.3] years old at time of completing the PAQ. Median PAQ score was 2.2 [1.7-2.9]. There were no significant differences in PAQ scores between organ transplant type or between genders. Lower PAQ score was associated with sensory disability (9 vs 49 without disability; P = <.01) and age at time of completing the PAQ (r = -.50, P = <.01). These results suggest that older age at time of completing the PAQ and presence of sensory disability may influence PA levels in the pediatric SOT population.

Province-wide Biliary Atresia Home Screening Program in British Columbia: Evaluation of First 2 Years.

BACKGROUND AND OBJECTIVES: Biliary atresia (BA), a rare newborn liver disease, is the leading cause of liver-related death in children. Early disease recognition and timely surgical Kasai hepatoportoenterostomy (KP) offers long-term survival without liver transplant. Universal BA screening in Taiwan using infant stool color cards (ISCCs) has proven effectiveness. We report our experience with infant stool color card (ISCC) BA screening in a province-wide program in British Columbia (BC). The objective of this study is to assess program performance and cost from launch April 1, 2014 to March 31, 2016. METHODS: ISCCs distributed to families upon maternity ward discharge. Parents were instructed to monitor their infant's stool color for 1 month and contacted the screening center with concerns. The number of live births, ISCC distribution, BA cases, and costs were recorded. Cases with Program screen success had both acholic stool recognition (ISCC screen success) and timely referral for BA. RESULTS: All 126 maternity units received ISCCs. Of 87,583 live births there were 6 BA cases. Of the 5 cases with ISCC Screen Success 3 had Program Screen Success. The median KP age in the program screen success and failure groups was 49 (42-52) and 116 (49-184) days, respectively. Program sensitivity was 50%, specificity 99%, positive predictive value 4%, and negative predictive value 99%. A random sample of 1054 charts at BC Children's Hospital found an ISCC distribution rate of 94%. After a phase-in period, the annual program cost was $30,033.82, and the ISCC cost per birth was $0.68. CONCLUSIONS: The screening program has high specificity and distribution with low cost. Successful program case identification had earlier age at KP. Program modifications aim to improve sensitivity. Longer-term studies will determine program impact on health outcomes.

Prolonged granulocyte colony stimulating factor use in glycogen storage disease type 1b associated with acute myeloid leukemia and with shortened telomere length.

Glycogen storage disease (GSD) type 1 is a rare autosomal recessive inherited condition. The 1b subtype comprises the minority of cases, with an estimated prevalence of 1 in 500,000 children. Patients with glycogen storage disease type 1b are often treated with granulocyte colony stimulating factor (G-CSF) for prolonged periods to improve symptoms of inflammatory bowel disease (IBD) and in the face of severe neutropenia to decrease risk of infection. Long-term G-CSF treatment may result in an increased risk of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) possibly due to increased marrow stress resulting in telomere shortening. To our knowledge, there have been two published cases of AML in GSD type 1b patients following long-term G-CSF exposure. Here, we report two further cases of AML/MDS-related changes in patients GSD type 1b treated with G-CSF. One patient developed AML with complex karyotype after 20 years of G-CSF treatment. The second patient was found to have short telomeres after 10 years of G-CSF exposure, but no evidence of acute leukemia at present. The third patient developed AML/MDS after 25 years of G-CSF use, with short telomeres prior to bone marrow transplant. Together these cases suggest that GSD type 1b patients with prolonged G-CSF exposure may be at an increased risk of MDS/AML states associated with G-CSF-induced shortened telomeres. We recommend that any GSD1b patients with prolonged G-CSF should have routine telomere assessments with monitoring for MDS if telomere shortening is observed, and with particular attention warranted if there is unexplained loss of G-CSF responsiveness.

Antenatal Treatment with Intravenous Immunoglobulin to Prevent Gestational Alloimmune Liver Disease: Comparative Effectiveness of 14-Week versus 18-Week Initiation.

BACKGROUND: Antenatal therapy with high-dose intravenous immunoglobulin (IVIG) may prevent gestational alloimmune liver disease (GALD). OBJECTIVE: The objective of this study was to determine the effectiveness of this approach in a large cohort of women at risk for poor pregnancy outcome due to GALD. METHODS: Women with a history of affected offspring were provided antenatal IVIG treatment and data were acquired prospectively from 1997 to 2015. The outcomes of treated pregnancies were compared to those of untreated pregnancies, and the effectiveness of starting at 14 weeks was compared to that of starting at 18 weeks. RESULTS: A total of 188 treated pregnancies in 151 women were analyzed. Only 30% (n = 105) of untreated gestations resulted in healthy offspring as compared to 94% (n = 177) of treated pregnancies (p < 0.0001). Treated gestations of both the 14-week (n = 108) and the 18-week (n = 80) start cohort showed a decreased rate of fetal loss relative to untreated gestations (p < 0.0001). Equivalent outcomes were recorded in the 18-week versus the 14-week start cohort (p > 0.05). Few adverse events or complications of antenatal therapy were recorded. CONCLUSION: Antenatal therapy with high-dose IVIG initiated at either 18 or 14 gestational weeks effectively prevents poor outcome of pregnancies at risk for GALD.

A national retrospective study of paediatric end-stage liver disease as a predictor of change to second-line therapy in children with autoimmune hepatitis.

BACKGROUND & AIMS: Adult studies of autoimmune hepatitis (AIH) have shown that the model of end-stage liver disease is associated with resistance to first-line treatment. Using a multicentre retrospective database, we sought to determine if the paediatric end-stage liver disease (PELD) score would similarly predict treatment resistance in paediatric AIH. METHODS: One hundred and seventy-one children from 13 Canadian centres who fulfilled the International Autoimmune Hepatitis Group (IAIHG) criteria were included and assessed for change to second-line therapy within 24 months of primary treatment onset. Those with PSC overlap at presentation, or missing data on the PELD variables were excluded. PELD was calculated for all remaining patients. Univariate analysis and receiver-operator characteristic (ROC) curves were performed to determine the predictive ability of the PELD score to change to second-line therapy. RESULTS: A total of 103 children were included with median age of 11 years (range 2-17). Mean PELD was -2.51±8.58. Second-line therapy was used within 24 months of diagnosis in 13 patients. Univariate analysis revealed that change to second-line therapy was associated with higher PELD (P=.028) and internal normalized ratio (INR) (P=.011). ROC curves for PELD and its individual components were performed. The strength of association was strongest with INR (AUC 0.72; CI: 0.58-0.86) although the composite PELD score also showed some predictive ability (AUC 0.67; CI: 0.52-0.81). CONCLUSION: In this paediatric AIH cohort, higher PELD at presentation predicted change to second-line therapy within the first 2 years of follow-up. INR appeared to be the main contributor to that association.

Management of Pediatric Nonalcoholic Fatty Liver Disease by Academic Hepatologists in Canada: A Nationwide Survey.

BACKGROUND: The literature on the optimal clinical management of pediatric patients with nonalcoholic fatty liver disease (NAFLD) is limited. The objective of this study was to identify discrepancies in the care provided to patients with NAFLD by hepatologists practicing in academic centers across Canada. METHODS: A nationwide survey was distributed electronically to all pediatric hepatologists practicing in university-affiliated hospitals using the infrastructure of the Canadian Pediatric Hepatology Research Group. The responses were anonymous. RESULTS: The response rate to the survey was 79%. Everyone reported diagnosing NAFLD based on a combination of elevated transaminases and imaging suggestive of steatosis in the context of an otherwise negative workup for other liver diseases. Only 14% use liver biopsy to confirm the diagnosis. There are significant discrepancies in the frequency of screening for other comorbidities (eg, hypertension, sleep apnea, etc) and in the frequency of laboratory investigations (eg, lipid profile, transaminases, international normalized ratio, etc). Frequency of outpatient clinic follow-up varies significantly. Treatment is consistently based on lifestyle modifications; however, reported patient outcomes in terms of body mass index improvements are poor. CONCLUSIONS: There are significant discrepancies in the care provided to children with NAFLD by hepatologists practicing in academic centers across Canada.

Clinical Characteristics and Complications of Pediatric Liver Biopsy: A Single Centre Experience.

INTRODUCTION: Percutaneous liver biopsy (LB) is the gold standard method for evaluation and management of patients with liver disease. The purpose of this study was to characterize pediatric patients undergoing LB at British Columbia Children's Hospital, and to determine the rate and timing of complications following the procedure. MATERIAL AND METHODS: The medical records of all pediatric patients who underwent LB during a six-year retrospective study were reviewed to collect demographic and procedure-related data. RESULTS: 223 LBs were performed, and 179 of these biopsies were percutaneous or transjugular. Elevated liver enzymes and cholestasis together accounted for almost 70% of the indications for LB, and the histological analysis of liver tissue yielded a specific diagnosis in 89 % of the cases. There were no deaths and no major complications related to LB. The most frequent minor complication was pain (59% of LBs) and the other complications were bleeding-related and classified as minor. The vast majority of complications (88%) were recognized within 8 h of the LB. CONCLUSIONS: LB is a valuable and safe procedure in pediatric patients with a low rate of complications. Pediatric patients can be discharged home safely should no complications occur within the first 8-12 h after the procedure.

Biliary atresia and other cholestatic childhood diseases: Advances and future challenges.

Biliary Atresia and other cholestatic childhood diseases are rare conditions affecting the function and/or anatomy along the canalicular-bile duct continuum, characterised by onset of persistent cholestatic jaundice during the neonatal period. Biliary atresia (BA) is the most common among these, but still has an incidence of only 1 in 10-19,000 in Europe and North America. Other diseases such as the genetic conditions, Alagille syndrome (ALGS) and Progressive Familial Intrahepatic Cholestasis (PFIC), are less common. Choledochal malformations are amenable to surgical correction and require a high index of suspicion. The low incidence of such diseases hinder patient-based studies that include large cohorts, while the limited numbers of animal models of disease that recapitulate the spectrum of disease phenotypes hinders both basic research and the development of new treatments. Despite their individual rarity, collectively BA and other cholestatic childhood diseases are the commonest indications for liver transplantation during childhood. Here, we review the recent advances in basic research and clinical progress in these diseases, as well as the research needs. For the various diseases, we formulate current key questions and controversies and identify top priorities to guide future research.

Home-Based Screening for Biliary Atresia Using Infant Stool Color Cards in Canada: Quebec Feasibility Study.

OBJECTIVES: Biliary atresia (BA) is a leading cause of liver failure and liver transplantation in pediatrics. BA manifests by 3 weeks of life with jaundice and pale stools. Delayed diagnosis and surgical intervention with Kasai portoenterostomy after 3 months of age is significantly associated with poor prognosis for native liver survival. A national Taiwan infant stool color card (SCC) screening program has entirely eliminated late Kasai portoenterostomy >90 days of age and improved native liver survival. A recent large-scale prospective cohort study in British Columbia, Canada, indicated that distribution of SCC on the maternity ward was feasible, led to high utilization rate, and was cost-effective. The aim of the present study was to assess the generalizability of this screening strategy in another Canadian jurisdiction with a different sociodemographic profile. METHODS: An SCC was distributed to families of newborns discharged at St Mary's Hospital Center, Montreal, Quebec. Families were instructed to monitor their infant's stool color for 21 days and then complete and mail the SCC to the study center. Phone surveys to families who did not return cards were used to estimate total card utilization rate. RESULTS: Two thousand two hundred forty-six infants were eligible for inclusion; 99.9% were enrolled. Mail SCC return rate was 63.3%. No cases of BA were identified. All of the 118 families who completed the phone survey reported that they had utilized the SCC. Conservative and optimistic estimates for total card utilization rates were 82% and 100%, respectively. CONCLUSIONS: The high enrollment and utilization rates in this screening study strongly support the feasibility of implementing a Canadian SCC screening program to improve outcomes of children with BA.

The Canadian Biliary Atresia Registry: Improving the care of Canadian infants with biliary atresia.

Biliary atresia is the most common cause of end-stage liver disease and liver cirrhosis in children, and the leading indication for liver transplantation in the paediatric population. There is no cure for biliary atresia; however, timely diagnosis and early infant age at surgical intervention using the Kasai portoenterostomy optimize the prognosis. Late referral is a significant problem in Canada and elsewhere. There is also a lack of standardized care practices among treating centres in this country. Biliary atresia registries currently exist across Europe, Asia and the United States. They have provided important evidence-based information to initiate changes to biliary atresia care in their countries with improvements in outcome. The Canadian Biliary Atresia Registry was initiated in 2013 for the purpose of identifying best standards of care, enhancing public education, facilitating knowledge translation and advocating for novel national public health policy programs to improve the outcomes of Canadian infants with biliary atresia.

L'atrésie des voies biliaires est la principale cause d'insuffisance hépatique terminale et de cirrhose chez les enfants, et la première indication de transplantation du foie au sein de la population d'âge pédiatrique. Aucun traitement ne guérit l'atrésie des voies biliaires, mais un diagnostic rapide et le jeune âge du nourrisson au moment de l'intervention chirurgicale par hépato-porto-entérostomie de Kasai optimisent le pronostic. L'orientation tardive vers un spécialiste constitue un problème important au Canada et ailleurs. Par ailleurs, il n'existe pas de protocole de soins standardisés dans les centres de traitement du pays. On trouve des registres d'atrésie des voies biliaires en Europe, en Asie et aux États-Unis, lesquels ont fourni de l'information importante fondée sur des données probantes pour susciter des changements aux soins de cette affection dans ces pays et favoriser une amélioration des résultats. Le Registre canadien d'atrésie des voies biliaires a été créé en 2013 pour définir les meilleures normes de soins, améliorer l'éducation publique, favoriser le transfert des connaissances et prôner de nouveaux programmes de politiques en santé publique en vue d'améliorer le sort des nourrissons canadiens présentant une atrésie des voies biliaires.

Laboratory Test Names Matter: A Survey on What Works and What Doesn't Work for Orders and Results.

CONTEXT.­: Health care providers were surveyed to determine their ability to correctly decipher laboratory test names and their preferences for laboratory test names and result displays. OBJECTIVE.­: To confirm principles for laboratory test nomenclature and display and to compare and contrast the abilities and preferences of different provider groups for laboratory test names. DESIGN.­: Health care providers across different specialties and perspectives completed a survey of 38 questions, which included participant demographics, real-life examples of poorly named laboratory orders that they were asked to decipher, an assessment of vitamin D test name knowledge, their preferences for ideal names for tests, and their preferred display for test results. Participants were grouped and compared by profession, level of training, and the presence or absence of specialization in informatics and/or laboratory medicine. RESULTS.­: Participants struggled with poorly named tests, especially with less commonly ordered tests. Participants' knowledge of vitamin D analyte names was poor and consistent with prior published studies. The most commonly selected ideal names correlated positively with the percentage of the authors' previously developed naming rules (R = 0.54, P < .001). There was strong consensus across groups for the best result display. CONCLUSIONS.­: Poorly named laboratory tests are a significant source of provider confusion, and tests that are named according to the authors' naming rules as outlined in this article have the potential to improve test ordering and correct interpretation of results. Consensus among provider groups indicates that a single yet clear naming strategy for laboratory tests is achievable.

CLMP is required for intestinal development, and loss-of-function mutations cause congenital short-bowel syndrome.

BACKGROUND & AIMS: Short-bowel syndrome usually results from surgical resection of the small intestine for diseases such as intestinal atresias, volvulus, and necrotizing enterocolitis. Patients with congenital short-bowel syndrome (CSBS) are born with a substantial shortening of the small intestine, to a mean length of 50 cm, compared with a normal length at birth of 190-280 cm. They also are born with intestinal malrotation. Because CSBS occurs in many consanguineous families, it is considered to be an autosomal-recessive disorder. We aimed to identify and characterize the genetic factor causing CSBS. METHODS: We performed homozygosity mapping using 610,000 K single-nucleotide polymorphism arrays to analyze the genomes of 5 patients with CSBS. After identifying a gene causing the disease, we determined its expression pattern in human embryos. We also overexpressed forms of the gene product that were and were not associated with CSBS in Chinese Hamster Ovary and T84 cells and generated a zebrafish model of the disease. RESULTS: We identified loss-of-function mutations in Coxsackie- and adenovirus receptor-like membrane protein (CLMP) in CSBS patients. CLMP is a tight-junction-associated protein that is expressed in the intestine of human embryos throughout development. Mutations in CLMP prevented its normal localization to the cell membrane. Knock-down experiments in zebrafish resulted in general developmental defects, including shortening of the intestine and the absence of goblet cells. Because goblet cells are characteristic for the midintestine in zebrafish, which resembles the small intestine in human beings, the zebrafish model mimics CSBS. CONCLUSIONS: Loss-of-function mutations in CLMP cause CSBS in human beings, likely by interfering with tight-junction formation, which disrupts intestinal development. Furthermore, we developed a zebrafish model of CSBS.