Impact of genetic and non-genetic factors on phenotypic diversity in NBAS-associated disease.

Biallelic pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause a pleiotropic multisystem disorder. Three clinical subgroups have been defined correlating with the localisation of pathogenic variants in the NBAS gene: variants affecting the C-terminal region of NBAS result in SOPH syndrome (short stature, optic atrophy, Pelger-Huët anomaly), variants affecting the Sec 39 domain are associated with infantile liver failure syndrome type 2 (ILFS2) and variants affecting the ß-propeller domain give rise to a combined phenotype. However, there is still unexplained phenotypic diversity across the three subgroups, challenging the current concept of genotype-phenotype correlations in NBAS-associated disease. Therefore, besides examining the genetic influence, we aim to elucidate the potential impact of pre-symptomatic diagnosis, emergency management and other modifying variables on the clinical phenotype. We investigated genotype-phenotype correlations in individuals sharing the same genotypes (n = 30 individuals), and in those sharing the same missense variants with a loss-of-function variant in trans (n = 38 individuals). Effects of a pre-symptomatic diagnosis and emergency management on the severity of acute liver failure (ALF) episodes also were analysed, comparing liver function tests (ALAT, ASAT, INR) and mortality. A strong genotype-phenotype correlation was demonstrated in individuals sharing the same genotype; this was especially true for the ILFS2 subgroup. Genotype-phenotype correlation in patients sharing only one missense variant was still high, though at a lower level. Pre-symptomatic diagnosis in combination with an emergency management protocol leads to a trend of reduced severity of ALF. High genetic impact on clinical phenotype in NBAS-associated disease facilitates monitoring and management of affected patients sharing the same genotype. Pre-symptomatic diagnosis and an emergency management protocol do not prevent ALF but may reduce its clinical severity.

Children with Localized Crohn's Disease Benefit from Early Ileocecal Resection and Perioperative Anti-Tumor Necrosis Factor Therapy.

INTRODUCTION: In pediatric Crohn's disease ileocecal resection is performed reluctantly as postoperative recurrence is frequent. Anti-tumor necrosis factor (TNF) therapy reduces postoperative recurrence rates but increases the risk for infections. MATERIALS AND METHODS: We retrospectively reviewed pediatric Crohn's disease patients who underwent ileocecal resection in our center. We compared disease activity and z-scores for height, weight, and body mass index of patients, who continuously received perioperative anti-TNF therapy (TNF + ), with those who did not (TNF-). RESULTS: Of 29 patients (48% females), 13 and 16 were grouped to TNF+ and TNF-, respectively. Patients' characteristics did not differ between groups, except a longer follow-up time in TNF-. We saw significant postoperative improvement but no normalization in z-scores for weight (1.78 vs. 0.77, p < 0.001), body mass index (1.08 vs. 0.22, p < 0.001), and height (0.88 vs. 0.66, p < 0.001). Disease activity improved significantly more in patients receiving anti-TNF therapy (moderate improvement in 83% vs. 31%, p = 0.02). Endoscopic recurrence was more frequent in patients without anti-TNF therapy (80% vs. 20%; p = 0.023), but endoscopic follow-up was incomplete. There was no increase of infections under perioperative anti-TNF therapy (1 patient each; p = 1.000). CONCLUSION: In patients with localized Crohn's disease an ileocecal resection leads to short-term postoperative improvement of disease activity, body mass index, weight, and growth. For relevant catch-up growth an earlier intervention is necessary. Continuous perioperative anti-TNF therapy had no increased risk of perioperative infections.

Swallowing-related quality of life in children with oesophageal atresia: a national cohort study.

Swallowing and feeding disorders are a major concern for children with oesophageal atresia (OA) after primary or staged OA repair. Primary OA repair is associated with higher rates of short-term complications in preterm infants with very low birth weight (VLBW) or extreme low birth weight (ELBW). On the other hand, primary repair may have the benefit of early commencement of oral feedings. We hypothesize that also in the medium-term, swallowing-related quality of life is better after primary oesophageal repair. We conducted a prospective cross-sectional study on swallowing quality in a national cohort of former VLBW and ELBW children with OA, using the structured paediatric swallowing quality of life (pedSWAL-QOL) questionnaire. Results were correlated with surgical approach and baseline clinical data. Principal component analysis of pedSWAL-QOL domains was performed. In total, 44 complete data sets of 78 children were available. The mean age of children was 8.5 years (SD = 7.4), and 23 children (52%) had primary OA repair. The overall median pedSWAL-QOL score was 2 (IQR = 0-3), representing a high swallowing-related quality of life, independent of surgical technique (p = 0.086). Children with a history of intracranial haemorrhage (ICH) (p = 0.002) and those with VACTERL association (p = 0.008) had significantly decreased enjoyment with eating. In addition, children with VACTERL association had problems to find suitable foods (p = 0.04). CONCLUSION: In this national cohort of VLBW and ELBW preterm-born children with OA, swallowing-related quality of life is good, mostly independent of initial surgery. Children with OA and ICH or VACTERL association may require more intense support with feeding. WHAT IS KNOWN: • Dysphagia, resembling feeding and swallowing disorders, is common in children and adults with repaired oesophageal atresia. Nevertheless, dysphagia in children with oesophageal atresia decreases with age. • Parents of younger children suffer from increased anxiety and fear regarding eating and swallowing abilities of their children. WHAT IS NEW: • Swallowing-related quality of life in former preterm children with oesophageal atresia is good, independent of initial surgical approach (primary vs. staged repair), even in very low birth weight or extreme low birth weight infants. • Children suffering from VACTERL association or intracranial haemorrhage show decreased enjoyment with eating.

Severe consumptive hypothyroidism in hepatic hemangioendothelioma.

OBJECTIVES: Consumptive hypothyroidism may occur in hepatic hemangioendothelioma. The altered expression of deiodinases inactivates peripheral thyroid hormones. As a result, serum levels of free triiodothyronine and free thyroxine are reduced to varying degrees. There are no established recommendations for the dosage of sirolimus for this particular indication. We describe for the first time the course of treatment with low-dose sirolimus. CASE PRESENTATION: We present a 5-week-old infant with hepatic hemangioendothelioma and severe consumptive hypothyroidism. Due to hepatic infiltration he showed signs of right heart strain. Therapy of hemangioendothelioma was initiated with propranolol and, in the absence of response, methylprednisolone was added. Treatment was continued with low-dose sirolimus (due to side effects) and propranolol. Hypothyroidism was managed with levothyroxine and liothyronine. CONCLUSIONS: Consumptive hypothyroidism due to cutaneous hemangioma and hepatic hemangioendothelioma can be managed with propranolol and low-dose sirolimus. Treatment of severe hypothyroidism may require a combinational therapy by substitution of both T3 and T4.

Sarcopenia in Children with Solid Organ Tumors: An Instrumental Era.

Sarcopenia has recently been studied in both adults and children and was found to be a prognostic marker for adverse outcome in a variety of patient groups. Our research showed that sarcopenia is a relevant marker in predicting outcome in children with solid organ tumors, such as hepatoblastoma and neuroblastoma. This was especially true in very ill, high-risk groups. Children with cancer have a higher likelihood of ongoing loss of skeletal muscle mass due to a mismatch in energy intake and expenditure. Additionally, the effects of cancer therapy, hormonal alterations, chronic inflammation, multi-organ dysfunction, and a hypermetabolic state all contribute to a loss of skeletal muscle mass. Sarcopenia seems to be able to pinpoint this waste to a high degree in a new and objective way, making it an additional tool in predicting and improving outcome in children. This article focuses on the current state of sarcopenia in children with solid organ tumors. It details the pathophysiological mechanisms behind sarcopenia, highlighting the technical features of the available methods for measuring muscle mass, strength, and function, including artificial intelligence (AI)-based techniques. It also reviews the latest research on sarcopenia in children, focusing on children with solid organ tumors.

Epstein-Barr Virus Prevalence at Diagnosis and Seroconversion during Follow-Up in Pediatric Inflammatory Bowel Disease.

Primary Epstein-Barr virus infection in pediatric patients with inflammatory bowel disease during immunomodulation with thiopurines has been associated with increased risk for malignancies or hemophagocytic lymphohistiocytosis. We determined Epstein-Barr virus (EBV) seroprevalence at inflammatory bowel disease (IBD) diagnosis and seroconversion during follow-up in a large single center cohort of children with IBD. EBV serology results and patient characteristics were retrospectively retrieved from the hospital documentation system. EBV seronegative patients at IBD diagnosis were prospectively retested. We report on IBD patients with symptomatic active EBV infection and a complicated disease course, and those diagnosed with malignancy with respect to EBV status and drug exposure. Of 402 patients, 194 (48%) had available EBV serology results at time of IBD diagnosis at a median of 12 years (IQR 9-14 years). Thereof, 102 (53%) were EBV-positive. Of 92 EBV-negative patients, 66 were retested and 17% showed a seroconversion at a mean follow-up time of 4.3 years (SD 3 years). Three children treated with azathioprine experienced acute clinically relevant EBV infection 2, 2.5, and 4 years after IBD diagnosis, two developed signs of hemophagocytic lymphohistiocytosis. Three cases of malignancy occurred in the cohort, though none seemed to be triggered by EBV. In conclusion, almost 50% of pediatric IBD patients were EBV-naïve following diagnosis and may be at increased risk to develop severe EBV infection during immunosuppressive therapy, potentially associated with complications such as hemophagocytic lymphohistiocytosis or malignancy.

Total Psoas Muscle Area as a Marker for Sarcopenia Is Related to Outcome in Children With Neuroblastoma.

Background: Sarcopenia describes a generalized loss of skeletal muscle mass, strength, or function. Determined by measuring the total psoas muscle area (tPMA) on cross-sectional imaging, sarcopenia is an independent marker for poor post-surgical outcomes in adults and children. Children with cancer are at high risk for sarcopenia due to immobility, chemotherapy, and cachexia. We hypothesize that sarcopenic children with neuroblastoma are at higher risk for poor post-operative outcomes. Patients and Methods: Retrospective analysis of children with neuroblastoma ages 1-15 years who were treated at our hospital from 2008 to 2016 with follow-up through March 2021. Psoas muscle area (PMA) was measured from cross-sectional images, using computed tomography (CT) and magnetic resonance imaging (MRI) scans at lumbar disc levels L3-4 and L4-5. tPMA is the sum of the left and right PMA. Z-scores were calculated using age- and gender-specific reference values. Sarcopenia was defined as a tPMA z-score below -2. A correlation of tPMA z-scores and sarcopenia with clinical variables and outcome was performed. Results: One hundred and sixty-four children with workup for neuroblastoma were identified, and 101 children fulfilled inclusion criteria for further analysis, with a mean age of 3.92 years (SD 2.71 years). Mean tPMA z-score at L4-5 was -2.37 (SD 1.02). Correlation of tPMA z-score at L4-5 with weight-for-age z-score was moderate (r = 0.54; 95% CI, 0.38, 0.66). No association between sarcopenia and short-term outcome was observed. Sarcopenia had a sensitivity of 0.82 (95% CI, 0.62-0.93) and a specificity of 0.48 (95% CI 0.36-0.61) in predicting 5-year survival. In a multiple regression analysis, pre-operative sarcopenia, pre-operative chemotherapy in the NB2004 high-risk group, unfavorable tumor histology, and age at diagnosis were associated with 5-year survival after surgery, with hazard ratios of 4.18 (95% CI 1.01-17.26), 2.46 (95% CI 1.02-5.92), 2.39 (95% CI 1.03-5.54), and 1.01 (95% CI 1.00-1.03), respectively. Conclusion: In this study, the majority of children had low tPMA z-scores and sarcopenia was a risk factor for decreased 5-year survival in children with neuroblastoma. Therefore, we suggest measuring the tPMA from pre-surgical cross-sectional imaging as a biomarker for additional risk stratification in children with neuroblastoma.

Esophageal Perforation and EVAC in Pediatric Patients: A Case Series of Four Children.

Introduction: In pediatric patients, esophageal perforation (EP) is rare but associated with significant morbidity and mortality rates of up to 20-30%. In addition to standard treatment options, endoscopic esophageal vacuum-assisted closure (EVAC) therapy has shown promising results, especially in adult patients. Thus far, the only data on technical success and effectiveness of EVAC in pediatric patients were published in 2018 by Manfredi et al. at Boston Children's Hospital. The sparse data on EVAC in children indicates that this promising technique has been barely utilized in pediatric patients. More data are needed to evaluate efficacy and outcomes of this technique in pediatric patients. Method: We reviewed five cases of therapy using EVAC, ArgyleTM Replogle Suction Catheter (RSC), or both on pediatric patients with EP in our institution between October 2018 and April 2020. Results: Five patients with EP (median 3.4 years; 2 males) were treated with EVAC, RSC, or a combination. Complete closure of EP was not achieved after EVAC alone, though patients' health stabilized and inflammation and size of EP decreased after EVAC. Four patients then were treated with RSC until the EP healed. One patient needed surgery as the recurrent fistula did not heal sufficiently after 3 weeks of EVAC therapy. Two patients developed stenosis and were successfully treated with dilatations. One patient treated with RSC alone showed persistent EP after 5 weeks. Conclusion: EVAC in pediatric patients is technically feasible and a promising method to treat EP, regardless of the underlying cause. EVAC therapy can be terminated as soon as local inflammation and C-reactive protein levels decrease, even if the mucosa is not healed completely at that time. A promising subsequent treatment is RSC. An earlier switch to RSC can substantially reduce the need of anesthesia during subsequent treatments. Our findings indicate that EVAC is more effective than RSC alone. In some cases, EVAC can be used to improve the tissues condition in preparation for a re-do surgery. At 1 year after therapy, all but one patient demonstrated sufficient weight gain. Further prospective studies with a larger cohort are required to confirm our observations from this small case series.

NBAS Variants Are Associated with Quantitative and Qualitative NK and B Cell Deficiency.

PURPOSE: Biallelic pathogenic NBAS variants manifest as a multisystem disorder with heterogeneous clinical phenotypes such as recurrent acute liver failure, growth retardation, and susceptibility to infections. This study explores how NBAS-associated disease affects cells of the innate and adaptive immune system. METHODS: Clinical and laboratory parameters were combined with functional multi-parametric immunophenotyping methods in fifteen NBAS-deficient patients to discover possible alterations in their immune system. RESULTS: Our study revealed reduced absolute numbers of mature CD56dim natural killer (NK) cells. Notably, the residual NK cell population in NBAS-deficient patients exerted a lower potential for activation and degranulation in response to K562 target cells, suggesting an NK cell-intrinsic role for NBAS in the release of cytotoxic granules. NBAS-deficient NK cell activation and degranulation was normalized upon pre-activation by IL-2 in vitro, suggesting that functional impairment was reversible. In addition, we observed a reduced number of naïve B cells in the peripheral blood associated with hypogammaglobulinemia. CONCLUSION: In summary, we demonstrate that pathogenic biallelic variants in NBAS are associated with dysfunctional NK cells as well as impaired adaptive humoral immunity.

Abatacept for treatment-refractory pediatric CTLA4-haploinsufficiency.

CTLA4-haploinsufficiency is a complex disease of immune dysregulation presenting with a broad spectrum of clinical manifestations. CTLA4-Fc fusion proteins such as abatacept have been described to alleviate immune dysregulation in several adult cases of CTLA4-haploinsufficiency. However, until now only few cases of pediatric CTLA4-haploinsufficiency treated with abatacept have been described. Here we present two pediatric cases of severe CTLA4-haploinsufficiency refractory to conventional immunosuppressive therapies that responded rapidly to treatment with abatacept. No side effects were observed during a follow-up period of 7-15 months. While one patient has successfully undergone HSCT the second patient continues to receive abatacept. Our cases demonstrate safe medium-term use of abatacept in the pediatric population.

Sarcopenia is a prognostic outcome marker in children with high-risk hepatoblastoma.

BACKGROUND: Children with hepatoblastoma (HB) are at risk of sarcopenia due to immobility, chemotherapy, and malnutrition. We hypothesized that children with HB have a low preoperative total psoas muscle area (tPMA), reflecting sarcopenia, which negatively impacts outcome. PROCEDURE: Retrospective study of children (1-10 years) with hepatoblastoma treated at a large university children's hospital from 2009 to 2018. tPMA was measured as the sum of the right and left psoas muscle area (PMA) at intervertebral disc levels L3-4 and L4-5. z-Scores were calculated using age- and gender-specific reference values and were compared to anthropometric measurements, clinical variables, and outcomes. Sarcopenia was defined as a tPMA z-score below -2. RESULTS: Thirty-three children were included. Mean tPMA z-score was -2.18 ± 1.08, and 52% were sarcopenic. A poor correlation between tPMA and weight was seen (r = 0.35; confidence interval [CI] 0.01, 0.62; P = .045), and most children had weights within the normal range (mean z-score -0.55 ± 1.39). All children categorized as high risk with relapse (n = 5/12) were sarcopenic before surgery. Relapse was significantly higher in the high-risk sarcopenic group compared to the nonsarcopenic group (P = .008). The change in tPMA z-score 1-4 months after surgery did not improve in patients with relapse, but did improve in 75% of children without relapse. CONCLUSIONS: The majority of children with HB were sarcopenic prior to surgery. Especially in children with high-risk hepatoblastoma, sarcopenia is an additional risk factor for relapse. Large multicenter studies are needed to confirm these preliminary results.

Diaphragmatic Hernia following Pediatric Liver Transplantation: An Underappreciated Complication Prone to Recur.

INTRODUCTION: Postoperative diaphragmatic hernia (DH) is a rare but potentially life-threatening complication following pediatric liver transplantation (LT). In the current literature, a total of 49 such hernias have been reported in 17 case series. We present eight additional cases, three of which reoccurred after surgical correction, and review the current literature with a focus on recurrence. MATERIALS AND METHODS: The study sample included children (<18 years of age) who underwent LT between June 2013 and June 2020 at five large transplant centers and who subsequently presented with DH. During the study period, a total of 907 LT was performed. Eight DH were recognized, and risk factors were analyzed. RESULTS: For the eight children with DH, the mean age at LT was 28.0 (5-132) months. All patients with a DH received left lateral segment split grafts except one, who received a full left lobe. The mean weight at time of LT was 11.8 (6.6-34) kg. Two patients had a primary abdominal muscle closure, and six had a temporary silastic mesh closure. All eight children presented with a right posterolateral DH. The small bowel was herniated in the majority of cases. Symptoms reported included nausea, vomiting, and respiratory distress. Two patients were asymptomatic, and discovery was incidental. All patients underwent prompt primary surgical repair. Three DH hernias (37.5%) recurred despite successful surgical correction. CONCLUSION: DH following liver transplant with technical variant grafts may be underreported and is prone to recur despite surgical correction. A better understanding of the pathophysiology and more thorough reporting may help increase awareness. Early detection and prompt surgical management are the cornerstones of a successful outcome.

Outcome of Patients With Esophageal Atresia and Very Low Birth Weight (≤ 1,500 g).

Introduction: Primary repair of esophageal atresia (EA) in infants with very low birth weight (VLBW) and extremely low birth weight (ELBW) has been widely performed in pediatric surgery. However, several studies have shown that complication rates in infants with VLBW are high. We hypothesize preterm children benefit from a shorter, less-traumatizing operation in the first days of life, as staged repair implies. Methods: Patients with EA and VLBW were retrieved from the database of a large national patient organization KEKS e.V. Structured questionnaires were sent to all the patients' families; the responses were pseudonymized and sent to our institution. Results: Forty-eight questionnaires from patients were analyzed. The mean birth weight was 1,223 g (720-1,500 g). Primary repair was performed in 25 patients (52%). Anastomotic insufficiency (AI) was reported in 9 patients (19%), recurrent fistula (RF) in 8 (17%), and anastomotic stenosis in 24 patients (50%). Although AI was almost twice as common after primary repair than after staged repair (24 vs. 13%; p = 0.5), the difference was not statistically significant. RF was more frequent after primary repair (28 vs. 4%; p = 0.04), gastroesophageal reflux was more frequent in the group after staged repair (78 vs. 52%; p = 0.04), and both correlations were statistically significant. Intracranial hemorrhage (ICH) was reported in 11 patients (23%) and was observed in 7 of them (64%, p = 0.4) after primary repair. ICH was reported in 60% of patients with ELBW and 75% of patients when ELBW was paired with primary repair. Conclusion: This study demonstrates the complication rate in patients with VLBW is higher than the average of that in patients with EA. The study indicates that a staged approach may be an option in this specific patient group, as less RF and AI are seen after staged repair. ICH rate in patients with ELBW seemed to be especially lower after staged repair. Interestingly, gastroesophageal reflux was statistically significantly higher in the group after staged repair, and postoperative ventilation time was longer. It is therefore necessary to individually consider which surgical approach is appropriate for this special patient group.

Paediatric reference values for total psoas muscle area.

BACKGROUND: Sarcopenia, the unintentional loss of skeletal muscle mass, is associated with poor outcomes in adult patient populations. In adults, sarcopenia is often ascertained by cross-sectional imaging of the psoas muscle area (PMA). Although children with chronic medical illnesses may be at increased risk for muscle loss because of nutritional deficiencies, physical deconditioning, endocrine anomalies, and systemic inflammation, consistent quantitative definitions for sarcopenia in children are lacking. We aimed to generate paediatric reference values for PMA at two intervertebral lumbar levels, L3-4 and L4-5. METHODS: In this cross-sectional study, we analysed abdominal computed tomography scans of consecutive children presenting to the emergency department. Participants were children 1-16 years who required abdominal cross-sectional imaging after paediatric trauma between January 1, 2005 and December 31, 2015 in a large Canadian quaternary care centre. Children with a documented chronic medical illness or an acute spinal trauma at presentation were excluded. Total PMA (tPMA) at levels L3-4 and L4-5 were measured in square millimetres (mm2 ) as the sum of left and right PMA. Age-specific and sex-specific tPMA percentile curves were modelled using quantile regression. RESULTS: Computed tomography images from 779 children were included. Values of tPMA at L4-5 were significantly larger than at L3-4 at all ages, but their correlation was high for both girls (r = 0.95) and boys (r = 0.98). Amongst girls, tPMA 50th percentile values ranged from 365 to 2336 mm2 at L3-4 and from 447 to 2704 mm2 for L4-5. Amongst boys, 50th percentile values for tPMA ranged between 394 and 3050 mm2 at L3-4 and from 498 to 3513 mm2 at L4-5. Intraclass correlation coefficients were excellent at L3-4 (0.97, 95% CI 0.94 to 0.981) and L4-5 (0.99, 95% CI 0.986 to 0.995). Weight and tPMA were correlated, stratified by sex for boys (L3-4 r = 0.90; L4-5 r = 0.90) and for girls (L3-4 r = 0.87; L4-5 r = 0.87). An online application was subsequently developed to easily calculate age-specific and sex-specific z-scores and percentiles. CONCLUSIONS: We provide novel paediatric age-specific and sex-specific growth curves for tPMA at intervertebral L3-4 and L4-5 levels for children between the ages of 1-16 years. Together with an online tool (https://ahrc-apps.shinyapps.io/sarcopenia/), these tPMA curves should serve as a reference enabling earlier identification and targeted intervention of sarcopenia in children with chronic medical conditions.

Defining clinical subgroups and genotype-phenotype correlations in NBAS-associated disease across 110 patients.

PURPOSE: Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis. METHODS: Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods. RESULTS: One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the ß-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: ß-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger-Huët anomaly/SOPH). CONCLUSION: We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.

Pulse wave velocity measurement as a marker of arterial stiffness in pediatric inflammatory bowel disease: a pilot study.

In adults with inflammatory bowel disease (IBD), the incidence of cardiovascular events is increased, leading to long-term morbidity. Arterial stiffness (AS) measured by pulse wave velocity (PWV) is a validated early precursor of cardiovascular disease (CVD), and measurement of PWV was shown to be a feasible test in children. The aim of this study was to assess AS in children with IBD. In this prospective study, we determined PWV between the carotid and femoral artery (PWVcf) in 25 children and adolescents with IBD (11 females, median age 14.1 years, median disease duration 2.8 years). The majority (68%) of the subjects were in clinical remission, and 48% received anti-tumor necrosis factor alpha (TNFα) treatment. AS was not increased in this cohort of children and adolescents with IBD, who did not have signs of cardiovascular disease, such as arterial hypertension. CONCLUSION: PWV seems to be normal in children with IBD in remission or with mild disease activity. Larger studies should assess its potential role as a valid and non-invasive follow-up marker in children with IBD, to avoid cardiovascular complications. What is Known : • Inflammatory bowel disease (IBD) is a risk factor of cardiovascular disease (CVD). • Pulse wave velocity (PWV) measurement is the current gold standard to assess arterial stiffness (AS), which is an early predictor of CVD. What is New: • This is the first study using PWV measurements to determine AS in children with IBD. • In children with IBD in remission or only mild disease activity AS is not increased.

Clinical presentation of celiac disease and the diagnostic accuracy of serologic markers in children.

There has been growing recognition of a changing clinical presentation of celiac disease (CD), with the manifestation of milder symptoms. Serologic testing is widely used to screen patients with suspected CD and populations at risk. The aim of this retrospective analysis was to evaluate the clinical presentation of CD in childhood, assess the diagnostic value of serologic tests, and investigate the impact of IgA deficiency on diagnostic accuracy. We evaluated 206 consecutive children with suspected CD on the basis of clinical symptoms and positive serology results. Ninety-four (46%) had biopsy-proven CD. The median age at diagnosis of CD was 6.8 years; 15% of the children were <2 years of age. There was a higher incidence of CD in girls (p = 0.003). Iron deficiency and intestinal complaints were more frequent in children with CD than those without CD (61% vs. 33%, p = 0.0001 and 71% vs. 55%, p = 0.02, respectively), while failure to thrive was less common (35% vs. 53%, p = 0.02). The sensitivity of IgA tissue transglutaminase (IgA-tTG) was 0.98 when including all children and 1.00 after excluding children with selective IgA deficiency. The specificity of IgA-tTG was 0.73 using the recommended cut-off value of 20 IU, and this improved to 0.94 when using a higher cut-off value of 100 IU. All children with CD and relative IgA deficiency (IgA levels that are measurable but below the age reference [n = 8]) had elevated IgA-tTG. In conclusion, CD is frequently diagnosed in school-age children with relatively mild symptoms. The absence of intestinal symptoms does not preclude the diagnosis of CD; many children with CD do not report intestinal symptoms. While the sensitivity of IgA-tTG is excellent, its specificity is insufficient for the diagnostic confirmation of a disease requiring life-long dietary restrictions. Children with negative IgA-tTG and decreased but measurable IgA values are unlikely to have CD.