Vitamin C and folate status in hereditary fructose intolerance.

BACKGROUND: Hereditary fructose intolerance (HFI) is a rare inborn error of fructose metabolism caused by the deficiency of aldolase B. Since treatment consists of a fructose-, sucrose- and sorbitol-restrictive diet for life, patients are at risk of presenting vitamin deficiencies. Although there is no published data on the status of these vitamins in HFI patients, supplementation with vitamin C and folic acid is common. Therefore, the aim of this study was to assess vitamin C and folate status and supplementation practices in a nationwide cohort of HFI patients. METHODS: Vitamin C and folic acid dietary intake, supplementation and circulating levels were assessed in 32 HFI patients and 32 age- and sex-matched healthy controls. RESULTS: Most of the HFI participants presented vitamin C (96.7%) and folate (90%) dietary intake below the recommended population reference intake. Up to 69% received vitamin C and 50% folic acid supplementation. Among HFI patients, 15.6% presented vitamin C and 3.1% folate deficiency. The amount of vitamin C supplementation and plasma levels correlated positively (R = 0.443; p = 0.011). Interestingly, a higher percentage of non-supplemented HFI patients were vitamin C deficient when compared to supplemented HFI patients (30% vs. 9.1%; p = 0.01) and to healthy controls (30% vs. 3.1%; p < 0.001). CONCLUSIONS: Our results provide evidence for the first time supporting vitamin C supplementation in HFI. There is great heterogeneity in vitamin supplementation practices and, despite follow-up at specialised centres, vitamin C deficiency is common. Further research is warranted to establish optimal doses of vitamin C and the need for folic acid supplementation in HFI.

Transferrin Isoforms, Old but New Biomarkers in Hereditary Fructose Intolerance.

Hereditary Fructose Intolerance (HFI) is an autosomal recessive inborn error of metabolism characterised by the deficiency of the hepatic enzyme aldolase B. Its treatment consists in adopting a fructose-, sucrose-, and sorbitol (FSS)-restrictive diet for life. Untreated HFI patients present an abnormal transferrin (Tf) glycosylation pattern due to the inhibition of mannose-6-phosphate isomerase by fructose-1-phosphate. Hence, elevated serum carbohydrate-deficient Tf (CDT) may allow the prompt detection of HFI. The CDT values improve when an FSS-restrictive diet is followed; however, previous data on CDT and fructose intake correlation are inconsistent. Therefore, we examined the complete serum sialoTf profile and correlated it with FSS dietary intake and with hepatic parameters in a cohort of paediatric and adult fructosemic patients. To do so, the profiles of serum sialoTf from genetically diagnosed HFI patients on an FSS-restricted diet (n = 37) and their age-, sex- and body mass index-paired controls (n = 32) were analysed by capillary zone electrophoresis. We found that in HFI patients, asialoTf correlated with dietary intake of sucrose (R = 0.575, p < 0.001) and FSS (R = 0.475, p = 0.008), and that pentasialoTf+hexasialoTf negatively correlated with dietary intake of fructose (R = -0.386, p = 0.024) and FSS (R = -0.400, p = 0.019). In addition, the tetrasialoTf/disialoTf ratio truthfully differentiated treated HFI patients from healthy controls, with an area under the ROC curve (AUROC) of 0.97, 92% sensitivity, 94% specificity and 93% accuracy.

Metabolic Serendipities of Expanded Newborn Screening.

Incidental findings on newborn screening (NBS) are results that are not the target of screening within a given NBS program, but rather are found as a result of the screening and resulting diagnostic workup for that target. These findings may not have an immediate clinical impact on the newborn, but are sometimes an additional benefit of NBS programs and may be considered secondary targets of NBS programs. This work describes four case reports that had incidental findings on the NBS, which eventually led to the diagnosis of another metabolic disease instead of the one that was initially suspected. The first case was a new defect in the cationic amino acid transporter-2 (CAT-2), which was oriented as an arginase-1 deficiency in the newborn. The second case was a maternal glutaric aciduria type 1 (GA-1) that mimicked a carnitine transporter deficiency in the newborn. The third report was a case of lysinuric protein intolerance (LPI), which appeared as high levels of citrulline on the NBS. The fourth case was a mother with homocystinuria that was diagnosed during the biochemical study of vitamin B12 status. All cases provide new or interesting data that will help guide differential diagnosis in the future.

Análisis de la determinación de niveles de tiopurínicos en pacientes pediátricos con enfermedad inflamatoria intestinal / Laboratory determination of thiopurine levels in paediatric patients with inflammatory bowel disease

INTRODUCCIÓN Y OBJETIVOS: Las tiopurinas son fármacos muy empleados para el mantenimiento de la remisión en pacientes con enfermedad inflamatoria intestinal. Se conocen cuáles son los niveles plasmáticos óptimos, y existe controversia acerca de si reducen la necesidad de otros fármacos o son coste-efectivos. El objetivo de nuestro estudio fue describir el uso del tratamiento optimizado con tiopurínicos en pacientes pediátricos con enfermedad inflamatoria intestinal seguidos en nuestra unidad desde la implementación de la determinación de niveles de fármaco. MATERIAL Y MÉTODOS: Estudio descriptivo retrospectivo en el que se analizaron valores en plasma mediante cromatografía líquida de 6-tioguanina (6-TGN), 6-metilmercaptopurina (6-MMP) y sus cocientes, así como estado clínico y variables analíticas y demográficas de pacientes con enfermedad inflamatoria intestinal en seguimiento en nuestra unidad. RESULTADOS: Se incluyeron 72 pacientes y se realizaron 140 determinaciones de metabolitos. En el 61,5% de las determinaciones los niveles de 6-TGN se encontraban por debajo del rango terapéutico (en 7 casos debido a falta de adherencia terapéutica), y en el 7,4% de las de 6-MMP estaban en rango de toxicidad. Tras la determinación de 77 muestras se tomó alguna actitud derivada, procediéndose a la modificación de dosis, al cambio de formulación o a la suspensión del fármaco. Únicamente 9 pacientes escalaron a fármaco biológico (13,4% del total que estaban en monoterapia). No se encontró relación entre la actividad de la enfermedad y los niveles de tiopurínicos. CONCLUSIONES: En nuestra experiencia la monitorización de niveles de tiopurinas ayudó a modificar la dosis de fármaco que recibía el paciente, adecuando sus niveles terapéuticos y evitando potencialmente la adición de nuevos fármacos

INTRODUCTION AND OBJECTIVES: Thiopurines are drugs widely used in patients for the maintenance of remission in inflammatory bowel disease. The optimal plasma levels are known, but there is controversy about whether the need for other drugs is reduced or is cost-effective. The aim of this study is to describe the use of the optimised treatment with thiopurines in paediatric patients with inflammatory bowel disease followed up in this Unit since the introduction of determining the drug levels. MATERIAL AND METHODS: A descriptive retrospective study was conducted in which the plasma values of 6-thioguanine (6-TGN), 6-methyl-mercapto-purine (6-MMP), and their ratios were analysed using liquid chromatography. Other variables were collected, such as clinical status, analytical and demographic variables of patients with inflammatory bowel disease followed up in this Unit. RESULTS: A total of 72 patients were included, and 149 determinations of metabolites were performed. The 6-TGN levels were found to below the therapeutic range in 61.5% of patients (in 7 cases due to lack of adherence to therapy), and 6-MMP was in the toxicity range in 7.4%. After the determination of 77 specimens, some action was taken, such as modifying the dose, change of formula, or withdrawing the drug. Only 9 patients were scaled to a biological drug (13.4% of the total on single therapy). No association was found between the activity of the disease and the thiopurine levels. CONCLUSIONS: In our experience, the monitoring of thiopurine levels helped to modify the drug dose that the patient received, adjusting their therapeutic levels, and potentially avoiding the addition of new drugs

[Laboratory determination of thiopurine levels in paediatric patients with inflammatory bowel disease]. / Análisis de la determinación de niveles de tiopurínicos en pacientes pediátricos con enfermedad inflamatoria intestinal.

INTRODUCTION AND OBJECTIVES: Thiopurines are drugs widely used in patients for the maintenance of remission in inflammatory bowel disease. The optimal plasma levels are known, but there is controversy about whether the need for other drugs is reduced or is cost-effective. The aim of this study is to describe the use of the optimised treatment with thiopurines in paediatric patients with inflammatory bowel disease followed up in this Unit since the introduction of determining the drug levels. MATERIAL AND METHODS: A descriptive retrospective study was conducted in which the plasma values of 6-thioguanine (6-TGN), 6-methyl-mercapto-purine (6-MMP), and their ratios were analysed using liquid chromatography. Other variables were collected, such as clinical status, analytical and demographic variables of patients with inflammatory bowel disease followed up in this Unit. RESULTS: A total of 72 patients were included, and 149 determinations of metabolites were performed. The 6-TGN levels were found to below the therapeutic range in 61.5% of patients (in 7 cases due to lack of adherence to therapy), and 6-MMP was in the toxicity range in 7.4%. After the determination of 77 specimens, some action was taken, such as modifying the dose, change of formula, or withdrawing the drug. Only 9 patients were scaled to a biological drug (13.4% of the total on single therapy). No association was found between the activity of the disease and the thiopurine levels. CONCLUSIONS: In our experience, the monitoring of thiopurine levels helped to modify the drug dose that the patient received, adjusting their therapeutic levels, and potentially avoiding the addition of new drugs.

Central Venous Sinus Thrombosis in a Boy With Acute Severe Ulcerative Colitis.

Cerebral venous sinus thrombosis (CVST) in childhood is uncommon. Certain diseases predispose patients to CVST, such as inflammatory bowel disease (IBD), which is considered a risk factor for developing thrombosis, which in turn is considered an extraintestinal manifestation of IBD. The use of prophylaxis in certain patients is a controversial topic. We present the case of a 5-years-old child with ulcerative colitis, who presented with transverse sinus thrombosis immediately after colectomy. Considering the recent recommendations on prophylaxis in this disease, our patient and probably many others would benefit from establishing treatment with low-molecular-weight heparin. We believe that these recommendations should be known, with our case serving as an example, given that we are heading in a direction that has so far been controversial.

Colitis eosinofílica en pacientes pediátricos intervenidos de enfermedad de Hirschsprung / Eosinophilic colitis in children after surgery for Hirschsprung disease

Introducción: la colitis eosinofílica suele debutar con signos de enterocolitis, aunque hay casos descritos en los que se diagnostica tras episodios de obstrucción intestinal subaguda. Presentamos nuestra experiencia en niños diagnosticados de colitis eosinofílica que han sido intervenidos previamente de enfermedad de Hirschsprung. Resultados: 7 de los 44 pacientes intervenidos por enfermedad de Hirschsprung fueron diagnosticados de colitis eosinofílica. Mediana de edad de cirugía de enfermedad de Hirschsprung: tres meses; mediana de edad de colitis eosinofílica: 21 meses. Debutaron con diarrea mucosanguinolenta seis casos. Seis de siete niños presentaron cuadro de enteritis previo al diagnóstico de colitis eosinofílica y uno de siete rectorragia. El cribado infeccioso fue negativo en todos los casos. El diagnóstico de colitis eosinofílica mediante biopsia en todos los casos. Un paciente sin tratamiento, tres con fórmula elemental y solo dos con esteroides sistémicos (uno de ellos requirió cirugía finalmente). En todos los niños tratados se resolvió el cuadro, salvo en un caso que precisó instauración de nutrición parenteral y finalmente resección colónica con ileostomía. Conclusiones: en nuestra serie, hemos encontrado asociación entre enfermedad de Hirschsprung y colitis eosinofílica. En todos los casos se ha encontrado relación temporal entre ambas patologías, siendo siempre el diagnóstico de colitis eosinofílica posterior a la intervención quirúrgica por enfermedad de Hirschsprung. La exclusión de las proteínas de la leche de vaca y el empleo de antiinflamatorios han sido efectivos en la mayoría de los casos (AU)

Introduction: eosinophilic colitis tends to appear with signs of enterocolitis, although cases have been described after episodes of subacute intestinal obstruction. We present our experience in children diagnosed with eosinophilic colitis who had been previously operated for Hirschsprung disease. Results: 7 out of44 patients who underwent Hirschsprung disease were diagnosed with eosinophilic colitis. Median age of surgery for Hirschsprung disease was 3 months and the median age of diagnosis of eosinophilic colitis 21 months. Six cases debuted with diarrhea with blood. Six of seven children had enteritis prior to diagnosis of eosinophilic colitis and one of seven rectal bleeding. The infectious screening was negative in all cases.The diagnosis was performed by biopsy in all cases, compatible with eosinophilic colitis. Treatment: one patient did not require treatment, three children needed elemental formula and two patients systemic steroids (one of them finally required surgery). In all treated children the clinical picture was resolved, except in one case in which, given the persistence and impact of symptoms, required parenteral nutrition and finally colonic resection with ileostomy. Conclusions: In our series, we found some association between Hirschsprung disease and eosinophilic colitis. In all cases it was found a certain temporal relationship between the two diseases, always eosinophilic colitis after surgery for Hirschsprung disease. The exclusion of cow's milk proteins and the use of anti-inflammatory drugs have been effective in most cases (AU)

Enfermedad de Crohn metastásica en pediatría / Metastatic Crohn’s disease in pediatrics

Introducción: la enfermedad de Crohn metastásica (ECM) constituye una manifestación extraintestinal de la enfermedad de Crohn, siendo fundamental la biopsia para su diagnóstico. Existen referencias escasas a ECM en la edad pediátrica, y en adultos se estima una incidencia del 0,5-1%. No hay consenso sobre su abordaje terapéutico. Nuestro objetivo es describir nuestra experiencia diagnóstica y terapéutica en ECM. Caso clínico: se describen 4 casos de ECM en seguimiento en una Unidad de Gastroenterología Infantil en un hospital pediátrico de tercer nivel. Edades al diagnóstico entre 7 y 13 años. Las lesiones aparecieron antes del diagnóstico de enfermedad de Crohn (EC) en tres de ellos y durante la evolución de la enfermedad en otro. Localización genital en tres pacientes y en región pretibial bilateral en el otro. Todos demostraron granulomas no caseificantes en la biopsia. Dos pacientes precisaron únicamente nutrición enteral exclusiva, observándose resolución completa, mientras que otros dos recibieron terapias combinadas (corticoides, azatioprina, tacrolimus, infliximab y adalimumab) por recurrencia. Solo un caso requirió cirugía por mal control clínico. Discusión: la ECM es una entidad rara aunque siempre debemos incluirla en el diagnóstico diferencial de las lesiones cutáneas en enfermedad de Crohn, teniendo en cuenta que puede ser el debut de la enfermedad. Nos basaremos en la biopsia en cualquier caso para el diagnóstico definitivo. En esta serie se verifica la región genital como la más habitual en niños. El abordaje terapéutico no difiere del manejo de la afectación intestinal (AU)

Introduction and objectives: Metastatic Crohn’s disease (MCD) is an extraintestinal manifestation of Crohn’s disease, with biopsy as fundamental diagnostic tool. There are few references to MCD in children, with a 0.5-1% estimated incidence in adults. There is no consensus about its therapeutic approach. We describe our diagnostic and therapeutic experience in MCD. Results: Four cases of MCD are described in our Pediatric Gastroenterology Unit in a tertiary care hospital. The age at diagnosis was between 7 and 13 years. Lesions appeared before the diagnosis of Crohn’s disease in three of them, and during the course of the disease in another one, with genital location in three patients and bilateral pretibial region in the other. All four cases demonstrated non-caseificant granulomas on biopsy. Only two patients used exclusive enteral nutrition therapy with complete resolution, while other two cases received a combination of therapies (corticosteroids, azathioprine, tacrolimus, infliximab and adalimumab) because of recurrence. Only one case required surgery after poor clinical control. Conclusion: The MCD is infrequent but must always be included in the differential diagnosis of cutaneous lesions in Crohn’s disease, considering it could be the debut of the disease. We will rely on biopsy anyway for definitive diagnosis. In this series the genital region is verified as the most commonly affected in children. The therapeutic approach does not differ from the management of intestinal involvement (AU)

Metastatic Crohn's disease in pediatrics.

INTRODUCTION AND OBJECTIVES: Metastatic Crohn's disease (MCD) is an extraintestinal manifestation of Crohn's disease, with biopsy as fundamental diagnostic tool. There are few references to MCD in children, with a 0.5-1% estimated incidence in adults. There is no consensus about its therapeutic approach. We describe our diagnostic and therapeutic experience in MCD. RESULTS: Four cases of MCD are described in our Pediatric Gastroenterology Unit in a tertiary care hospital. The age at diagnosis was between 7 and 13 years. Lesions appeared before the diagnosis of Crohn's disease in three of them, and during the course of the disease in another one, with genital location in three patients and bilateral pretibial region in the other. All four cases demonstrated non-caseificant granulomas on biopsy. Only two patients used exclusive enteral nutrition therapy with complete resolution, while other two cases received a combination of therapies (corticosteroids, azathioprine, tacrolimus, infliximab and adalimumab) because of recurrence. Only one case required surgery after poor clinical control. CONCLUSION: The MCD is infrequent but must always be included in the differential diagnosis of cutaneous lesions in Crohn's disease, considering it could be the debut of the disease. We will rely on biopsy anyway for definitive diagnosis. In this series the genital region is verified as the most commonly affected in children. The therapeutic approach does not differ from the management of intestinal involvement.

Urea cycle disorders in Spain: an observational, cross-sectional and multicentric study of 104 cases.

BACKGROUND: Advances in the diagnosis and treatment of urea cycle disorders (UCDs) have led to a higher survival rate. The purpose of this study is to describe the characteristics of patients with urea cycle disorders in Spain. METHODS: Observational, cross-sectional and multicenter study. Clinical, biochemical and genetic data were collected from patients with UCDs, treated in the metabolic diseases centers in Spain between February 2012 and February 2013, covering the entire Spanish population. Heterozygous mothers of patients with OTC deficiency were only included if they were on treatment due to being symptomatic or having biochemistry abnormalities. RESULTS: 104 patients from 98 families were included. Ornithine transcarbamylase deficiency was the most frequent condition (64.4%) (61.2% female) followed by type 1 citrullinemia (21.1%) and argininosuccinic aciduria (9.6%). Only 13 patients (12.5%) were diagnosed in a pre-symptomatic state. 63% of the cases presented with type intoxication encephalopathy. The median ammonia level at onset was 298 µmol/L (169-615). The genotype of 75 patients is known, with 18 new mutations having been described. During the data collection period four patients died, three of them in the early days of life. The median current age is 9.96 years (5.29-18), with 25 patients over 18 years of age. Anthropometric data, expressed as median and z-score for the Spanish population is shown. 52.5% of the cases present neurological sequelae, which have been linked to the type of disease, neonatal onset, hepatic failure at diagnosis and ammonia values at diagnosis. 93 patients are following a protein restrictive diet, 0.84 g/kg/day (0.67-1.10), 50 are receiving essential amino acid supplements, 0.25 g/kg/day (0.20-0.45), 58 arginine, 156 mg/kg/day (109-305) and 45 citrulline, 150 mg/kg/day (105-199). 65 patients are being treated with drugs: 4 with sodium benzoate, 50 with sodium phenylbutyrate, 10 with both drugs and 1 with carglumic acid. CONCLUSIONS: Studies like this make it possible to analyze the frequency, natural history and clinical practices in the area of rare diseases, with the purpose of knowing the needs of the patients and thus planning their care.

Esophageal multichannel intraluminal impedance and pH testing in the study of apparent life threatening episode incidents in infants.

INTRODUCTION: The conventional 24-hour pH monitoring is the gold standard for the diagnosis of gastro-esophageal reflux (GER), a possible cause of Apparent Life Threatening Episodes (ALTE). However, multichannel intraluminal impedance (MII) may provide advantages. OBJECTIVES: Comparison of the results of MII and pH monitoring in patients undergoing MII-pH monitoring in the 3-year study period because of having suffered from ALTE. MATERIAL AND METHODS: Prospective study of MII-pH monitoring performed in our unit to infants < 12 months of ageadmitted for ALTE for a 3-year period. RESULTS: Thirty nine patients studied. 2,692 pH monitoring episodes, with median of 24 (IQ: 15-44) episodes/patient, 1.30 (IQ: 0.80-2.60) reflux/hour, 1 (IQ: 0-4) reflux episode > 5 min per patient and clearance of 1.20 (IQ: 0.70-2.20) min/reflux. With pH monitoring analysis, 14 children (35.9 %) could have been diagnosed as GER (8 mild, 4 moderate and 2 severe) based on the classical criteria. MII identified a total of 8,895 events; only 3,219 among them were refluxes, with a median of 75 (IQ: 54-111) per patient, 1.30 (IQ: 1.3-2.6) episodes/hour). With MII-pH monitoring combination there were 21.60 (SD 15.21) acid reflux episodes, 67.33 weekly acid (SD 32.09) and 3.34 (SD 7.23) non-acid, being finally diagnosed 33 patients as GER. CONCLUSIONS: The association of pH monitoring and MII provides additional information that improves GER diagnostic performance without posing any additional risk to the infant patient. The non-acid/weekly acid refluxes, not detected by pH monitoring, account for a high percentage of episodes, this may have diagnostic and therapeutic significance, especially in infants. Further studies are needed to assess the normality of MMI in pediatric patients.

Impedanciometría esofágica multicanal y pHmetría en el estudio del episodio de riesgo vital aparente del lactante / Esophageal multichannel intraluminal impedance and pH-testing in the study of apparent life threatening episode incidents in infants

Introducción: la pHmetría convencional de 24 horas constituye el patrón de oro para el diagnóstico de episodios de riesgo vital aparente (ALTE). La impedanciometría intraluminal multicanal (IIM) puede aportar ventajas en el lactante. Objetivos: comparación de los resultados de IIM y pHmetría en los pacientes sometidos a IIM-pHmetría en el periodo de estudio por causa de estudio de ALTE. Material y métodos: estudio retrospectivo de IIM-pHmetrías realizadas en nuestro servicio a lactantes < 12 meses de edad ingresados por ALTE durante tres años. Resultados: 39 pacientes estudiados. La pHmetría registró 2.692 reflujos, con medianas de 24 (IQ: 15-44) reflujos/paciente, índice de reflujo de 1,30 (IQ: 0,80-2,60) reflujos/hora, 1 (IQ: 0-4) episodio de reflujo > 5 min por paciente y aclaramiento de 1,20 (IQ: 0,70-2,20) min/reflujo. Por pHmetría 14 niños (35,9 %) fueron diagnosticados de RGE. Mediante IIM se registraron 8.895 eventos; 3.219 fueron reflujos, con mediana de 75 (IQ: 54-111) reflujos/ paciente, 1,30 (IQ: 1,3-2,6) reflujos/hora. Mediante IIM-pHmetría, la media de reflujos ácidos por paciente fue de 21,60 (DE 15,21), débilmente ácidos 67,33 (DE 32,09) y no ácidos 3,34 (DE 7,23), pudiéndose diagnosticar finalmente a 33 pacientes de RGE. Conclusiones: la asociación de IMM y pHmetría proporciona información adicional que mejora el rendimiento diagnóstico, sin suponer ningún riesgo adicional para el paciente. Los reflujos no ácidos/débilmente ácidos, los cuales no son detectados mediante pHmetría, suponen un porcentaje elevado, sobre todo en lactantes; esto tiene gran importancia diagnóstica en el estudio del ALTE. Aún son necesarios estudios para valorar la normalidad en IIM en pacientes pediátricos (AU)

Introduction: The conventional 24-hour pH monitoring is the gold standard for the diagnosis of gastro-esophageal reflux (GER), a possible cause of Apparent Life Threatening Episodes (ALTE). However, multichannel intraluminal impedance (MII) may provide advantages. Objectives: Comparison of the results of MII and pH monitoring in patients undergoing MII-pH monitoring in the 3-year study period because of having suffered from ALTE. Material and methods: Prospective study of MII-pH monitoring performed in our unit to infants < 12 months of age admitted for ALTE for a 3-year period. Results: Thirty nine patients studied. 2,692 pH monitoring episodes, with median of 24 (IQ: 15-44) episodes/patient, 1.30 (IQ: 0.80-2.60) reflux/hour, 1 (IQ: 0-4) reflux episode > 5 min per patient and clearance of 1.20 (IQ: 0.70-2.20) min/reflux. With pH monitoring analysis, 14 children (35.9 %) could have been diagnosed as GER (8 mild, 4 moderate and 2 severe) based on the classical criteria. MII identified a total of 8,895 events; only 3,219 among them were refluxes, with a median of 75 (IQ: 54-111) per patient, 1.30 (IQ: 1.3-2.6) episodes/hour). With MII-pH monitoring combination there were 21.60 (SD 15.21) acid reflux episodes, 67.33 weekly acid (SD 32.09) and 3.34 (SD 7.23) non-acid, being finally diagnosed 33 patients as GER. Conclusions: The association of pH monitoring and MII provides additional information that improves GER diagnostic performance without posing any additional risk to the infant patient. The non-acid/weekly acid refluxes, not detected by pH monitoring, account for a high percentage of episodes, this may have diagnostic and therapeutic significance, especially in infants. Further studies are needed to assess the normality of MMI in pediatric patients (AU)