Chronic diarrhoea due to trichohepatoenteric syndrome (THES) in an infant.

An infant was admitted with suspected postinfectious malabsorption with watery diarrhoea, fever and failure to thrive. She had dehydration, acute kidney injury and metabolic acidosis, which were corrected with intravenous fluids and managed with empiric antibiotics and prophylactic antifungals. She also developed Escherichia coli sepsis, meningitis and Candida skin infections during hospitalisation, which were treated according to the culture reports. Intrauterine growth restriction, woolly hair and a broad nasal bridge with chronic refractory diarrhoea prompted genetic testing to rule out syndromic diarrhoea. Whole-exome sequencing revealed a pathogenic compound heterozygous mutation causing trichohepatoenteric syndrome. She succumbed to severe infections at 80 days of life. The condition is rare, and no established guidelines or specific treatments exist; the focus is to promote optimal growth through parenteral nutrition, elemental formula and infection control. Early suspicion and molecular genetic testing can help reduce the time to diagnosis, treatment and genetic counselling.

Long term outcomes in children with trichohepatoenteric syndrome.

Trichohepatoenteric syndrome (THES) is a rare autosomal recessive disorder caused by mutations in either TTC37 or SKIV2L, usually leading to congenital diarrhea as part of a multisystem disease. Here, we report on the natural history of the disease for the largest UK cohort of patients with THES from 1996 to 2020. We systematically reviewed the clinical records and pathological specimens of patients diagnosed with THES managed in a single tertiary pediatric gastroenterology unit. Between 1996 and 2020, 13 patients (7 female and 6 male) were diagnosed with THES either by mutation analysis or by clinical phenotype. Two patients died from complications of infection. All patients received parenteral nutrition (PN) of which six patients were weaned off PN. All patients had gastrointestinal tract inflammation on endoscopy. Almost half of the cohort were diagnosed with monogenic inflammatory bowel disease (IBD) by the age of 11 years, confirmed by endoscopic and histological findings. Protracted diarrhea causing intestinal failure improves with time in all patients with THES, but monogenic IBD develops in later childhood that is refractory to conventional IBD treatments. Respiratory issues contribute to significant morbidity and mortality, and good respiratory care is crucial to prevent comorbidity.

Diarrea grave en una lactante previamente sana: un reto diagnóstico / Severe diarrhoea in a previously healthy infant: a diagnostic challenge

Aunque la causa más frecuente de los procesos diarreicos infantiles son las infecciones, ante cuadros graves y prolongados en el tiempo en los lactantes hay que descartar causas congénitas como trastornos genéticos o inmunodeficiencias. La colitis por citomegalovirus (CMV) es una causa poco frecuente de diarrea crónica en niños inmunocompetentes. Por lo general, su curso es leve y autolimitado, por lo que debemos pensar la posibilidad de que exista una inmunodeficiencia en los casos con una evolución más grave. Se recomienda realizar un estudio endoscópico en estos pacientes, precisando tratamiento antiviral aquellos con un curso de la enfermedad más grave o en caso de confirmarse situación de inmunodepresión (AU)

Although the most frequent cause of childhood diarrheal processes is infection, in the case of severe and prolonged symptoms in infants, congenital causes such as genetic disorders or immunodeficiencies must be ruled out. Cytomegalovirus (CMV) colitis is a rare cause of chronic diarrhoea in immunocompetent children. In general, it is a mild and self-limiting disease, so the possibility of immunodeficiency should be considered in cases with a more severe course. Performance of an endoscopic examination is recommended in these patients, and antiviral treatment is required in those with more severe forms of disease or with confirmed immunosuppression. (AU)

Use of TaqMan Array Cards to investigate the aetiological agents of diarrhoea among young infants with severe acute malnutrition.

OBJECTIVE: Studies involving less sensitive conventional microscopy and culture-based approaches have identified distinct differences in diarrhoeal aetiology in childhood malnutrition. Our study involved the use of an advanced molecular biology technique, the TaqMan Array Cards (TAC), to elucidate the diarrhoeal aetiology among young infants with severe acute malnutrition (SAM). METHOD: A total of 113 faecal samples was collected from SAM infants, aged 2-6 months, upon admission to the Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) with complications of diarrhoea and related comorbidities. We used TAC for the detection of 29 different diarrhoeal enteropathogens from a single faecal sample. For comparison, we also analysed 25 diarrhoeal samples from well-nourished infants of similar age. RESULTS: Higher odds of detection of all bacterial enteropathogens were associated with diarrhoea among SAM infants. In particular, the detection of Aeromonas sp (aOR: 25.7, p = 0.011), Campylobacter sp (aOR: 9.6, p < 0.01) and ETEC (aOR: 5.2, p = 0.022) was significantly associated with diarrhoea among SAM infants in comparison to well-nourished infants. 80% higher odds of detection of rotavirus and norovirus GII were associated with diarrhoea among well-nourished infants in comparison to SAM infants (aOR: 0.2, p < 0.05). CONCLUSION: Our study findings demonstrate a difference in diarrhoeal aetiology among SAM and well-nourished young infants, which may be useful in providing an evidence-based logic for possible revision of treatment guidelines for treatment of young diarrhoeal infants with SAM in the early management of the menace of antimicrobial resistance.

Congenital Diarrhea and Enteropathies in Infants: Approach to Diagnosis.

Congenital diarrhea and enteropathies (CODEs) are monogenic disorders causing early onset of intractable diarrhea. Their diagnosis and management are challenging. With the availability of commercial next generation genetic testing, we are now better able to classify and manage these disorders. The authors present their experience with 4 cases. Two patients had congenital tufting enteropathy (CTE) and 1 case each of microvillous inclusion disease (MVID) and trichohepatoenteric syndrome (THES). Age at onset varied from 3 to 38 d of life. Light microscopy and electron microscopy of duodenal and rectal endoscopic biopsies were consistent with the diagnosis. Genetic evaluation was possible in 3 cases indicating causative mutations. Two children (CTE and MVID) were alive at last follow-up. The authors suggest a stepwise approach to the diagnosis and management of these disorders in the Indian context.

Expanding the clinical spectrum in trichohepatoenteric syndrome.

Trichohepatoenteric syndrome (THES) is a very rare autosomal recessive genetic disorder, which is characterized by intractable diarrhea during infancy, dysmorphic features, immunodeficiency, and a failure to thrive. There are still significant difficulties for patients and clinicians in terms of the management of THES, even though its molecular basis has been uncovered in the last decade. In this article, we have presented two cases relating to siblings that have been diagnosed with the condition. Concerning one of the patients, we described a novel variation (c.2114 + 5G > A) in the TTC37 gene and a mild clinical course; meanwhile, the other one was clinically diagnosed with THES at 17 years of age, but they had seizures and died suddenly. These cases expand the spectrum of clinical findings in relation to THES.

Probióticos y prebióticos: rol en la terapéutica de la enfermedad diarreica aguda infantil / Probiotics and prebiotics: its role in childhood acute diarrheal disease therapy

RESUMEN: La enfermedad diarreica aguda infantil (EDAI), constituye un problema de salud pública, representando la 2ª causa de morbimortalidad infantil en menores de 5 años, en el Ecuador. La hidratación oral y parenteral en los niños hospitalizados bajo normas de administración de conformidad con el grado de deshidratación y pérdida de peso, así como medidas preventivas como la vacunación obligatoria contra el rotavirus, han contribuido a disminuir, pero no a solucionar este problema de salud infantil. Múltiples factores contribuyen para que no se resuelva: socioeconómicos, educacionales, el destete temprano y malas prácticas alimenticias, entre otros. Últimos estudios han propuesto la utilización de probióticos que contribuyan a disminuir el problema sugieriendo el usode Saccharomyces boulardii (SB), asociado a un prebiótico; lo que permitiría acortar el tiempo de tratamiento de una EDAI; por lo que la simbiosis entre SB y un prebiótico denominado fructooligosacárido (FOS), podría ser una alternativa para reducir costos y complicaciones. Una alternativa para medir el curso clínico de una EDAI en infantes es la escala BITTS, de reciente creación y fácil aplicación por clínicos. El objetivo de este manuscrito fue resumir la evidencia existente respecto del rol de losprobióticos y prebióticos en la terapéutica de de la EDAI.

SUMMARY: In Ecuador childhood acute diarrheal disease (CADD) constitutes a serious public health problem, representing the 2nd cause of infant morbidity and mortality in children under 5 years of age. Oral and parenteral hydration in hospitalized children, with standard treatments according to their degree of dehydration and weight loss, as well as preventive measures such as mandatory vaccination against rotavirus, have contributed to a decrease. Nevertheless, this childhood disease has still not been resolved. There are multiple contributing factors involved that prevent complete eradication of the disease Among these are socio-economic problems, education, early weaning and poor feeding practices, all of which continue to affect infants. Recent studies have proposed the use of probiotics that help reduce the problem and it has been suggested that Saccharomyces boulardii (SB), associated with a prebiotic, would reduce the treatment time of an CADD. Therefore, the symbiosis between the SB probiotic and a prebiotic called fructo- oligosaccharide (FOS) could be an alternative to reduce complications and reduce costs. An alternative to measure the clinical course of an CADD in infants is the BITTS scale, which was recently created and can easily be applied by clinicians. The aim of this manuscript was to summarize the existing evidence regarding the role of PROBIOTICS and prebiotics in the treatment of CADD.

Outcome associated with EPCAM founder mutation c.499dup in Qatar.

Tufting enteropathy (TE) is a rare autosomal recessive congenital enteropathy that usually requires long-term parenteral nutrition (PN). In the Arabic Peninsula, four distinct EPCAM mutations have been identified to cause TE. As consanguineous marriages are socially favored, pre-marital and pre-conception testing has become a critical disease prevention strategy. This study aimed to identify the pathogenic EPCAM mutations causing TE in Qatari families and determine possible genotype-phenotype correlations. Twenty-two TE patients from seven multiplex families with TE were identified. Blood samples were collected from patients and first-degree relatives. Exons of the gene were amplified and sequenced. Retrospective chart review and/or family interviews were conducted to determine phenotypic characteristics of the disease. Sequence analysis revealed a single, previously described c.499dup mutation in exon 5 of all families tested, suggesting a founder effect. Of the 18 patients whose full clinical information was available, three patients (17%) were off PN with a good quality of life, without intestinal transplantation, and one (6%) was receiving partial PN. Our patients with TE were severely stunted compared to a similar group of patients receiving long-term PN for short bowel syndrome, suggesting that this could possibly be due to TE rather than secondary to inadequate nutrition. Our study identified the EPCAM mutation c.499dup as the genetic defect causing TE in all the participant Qatari families. This finding should facilitate early diagnosis of TE and genetic counseling. Furthermore, it should aid in the prevention of TE through pre-marital screening, antenatal diagnosis, and pre-implantation genetic diagnosis.

Choque por dengue interpretado inicialmente como sepsis grave / Shock by dengue initially interpreted as severe sepsis

Introducción: La forma más frecuente de dengue grave es el choque por dengue. Sin embargo, los lactantes con dengue no presentan las manifestaciones clinicas que lo caracterizan ni tienen tan a menudo esta complicación como lo hacen los pacientes con edades mayores. Objetivo: Dar a conocer las características clinicas y laboratoriales de una paciente menor de un año de edad cuyo síndrome de choque por dengue fue interpretado inicialmente como un caso de sepsis grave. Presentación del caso: Paciente femenina de 8 meses de edad con fiebre y diarreas que concurre a más de un centro hospitalario y la madre se niega a ingresarla. Al quinto dia de enfermedad apareció exantema y ya estando afebril presenta cianosis y otros signos de hipoperfusión tissular, haciéndole diagnóstico inicial de choque por sepsis. Responde satisfactoriamente a la reposición de líquidos cristaloides por via intravenosa administrados inicialmente y es enviada despues a una unidad de terapia intensiva pediátrica donde continua recibiendo tratamiento de rehidratacion y se inicia antibioticoterapia. Posteriormente, la sepsis fue descartada por la evolución del caso y los resultados de laboratorio clinico y microbiológicos, asi como una serología positiva a dengue. Conclusiones. El choque por dengue en el lactante puede expresarse sin su cuadro clinico típico y para su diagnostico es imprescindible considerar el antecedente epidemiológico(AU).

Introduction: The most common form of severe dengue is the dengue shock syndrome. However, infants with dengue don´t present the clinical manifestations that characterize it neither have this complication as often as older patients do. Objective: To know the clinical and laboratory characteristics of a patient of less than one-year-old whose dengue shock syndrome was initially interpreted as a case of severe sepsis. Case presentation: 8-months-old female patient with fever and diarrhea that was checked in more than one hospital and the mother refuses to hospitalize her. In the fifth day of being ill appeared exanthem, and having fever she presented cyanosis and other signs of tisular hypoperfusion, being initially diagnosed a sepsis shock. She responded satisfactorily to the replacement of crystalloid fluids intravenously administered initially and she was sent to a pediatric intensive care unit where she continued receiving rehydration treatment and antibiotic therapy was started. Subsequently, sepsis was ruled out due to the case´s evolutions and the clinical and microbiological laboratory´s results, as well as a serology positive to dengue fever. Conclusions: Dengue shock syndrome in an infant can present without its typical clinical manifestations and for its diagnosis is essential to consider the epidemiological history(AU)

Tricho-hepatic-enteric syndrome (THES) without intractable diarrhoea.

Tricho-hepatic-enteric syndrome (THES) is a genetically heterogeneous rare syndrome (OMIM: 222470 (THES1) and 614602 (THES2)) that typically presents in the neonatal period with intractable diarrhoea, intra-uterine growth retardation (IUGR), facial dysmorphism, and hair and skin changes. THES is associated with pathogenic variants in either TTC37 or SKIV2L; both are components of the human SKI complex, an RNA exosome cofactor. We report an 8 year old girl who was diagnosed with THES by the Undiagnosed Disease Program-WA with compound heterozygous pathogenic variants in SKIV2L. While THES was considered in the differential diagnosis, the absence of protracted diarrhoea delayed definitive diagnosis. We therefore suggest that SKIV2L testing should be considered in cases otherwise suggestive of THES, but without the characteristic diarrhoea. We expand the phenotypic spectrum while reviewing the current knowledge on SKIV2L.

A novel TTC37 mutation causing clinical symptoms of trichohepatoenteric syndrome such as pyoderma gangrenosum and immunodeficiency without severe diarrhea

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Hydrometeorology and flood pulse dynamics drive diarrheal disease outbreaks and increase vulnerability to climate change in surface-water-dependent populations: A retrospective analysis.

BACKGROUND: The impacts of climate change on surface water, waterborne disease, and human health remain a growing area of concern, particularly in Africa, where diarrheal disease is one of the most important health threats to children under 5 years of age. Little is known about the role of surface water and annual flood dynamics (flood pulse) on waterborne disease and human health nor about the expected impact of climate change on surface-water-dependent populations. METHODS AND FINDINGS: Using the Chobe River in northern Botswana, a flood pulse river-floodplain system, we applied multimodel inference approaches assessing the influence of river height, water quality (bimonthly counts of Escherichia coli and total suspended solids [TSS], 2011-2017), and meteorological variability on weekly diarrheal case reports among children under 5 presenting to health facilities (n = 10 health facilities, January 2007-June 2017). We assessed diarrheal cases by clinical characteristics and season across age groups using monthly outpatient data (January 1998-June 2017). A strong seasonal pattern was identified, with 2 outbreaks occurring regularly in the wet and dry seasons. The timing of outbreaks diverged from that at the level of the country, where surface water is largely absent. Across age groups, the number of diarrheal cases was greater, on average, during the dry season. Demographic and clinical characteristics varied by season, underscoring the importance of environmental drivers. In the wet season, rainfall (8-week lag) had a significant influence on under-5 diarrhea, with a 10-mm increase in rainfall associated with an estimated 6.5% rise in the number of cases. Rainfall, minimum temperature, and river height were predictive of E. coli concentration, and increases in E. coli in the river were positively associated with diarrheal cases. In the dry season, river height (1-week lag) and maximum temperature (1- and 4-week lag) were significantly associated with diarrheal cases. During this period, a 1-meter drop in river height corresponded to an estimated 16.7% and 16.1% increase in reported diarrhea with a 1- and 4-week lag, respectively. In this region, as floodwaters receded from the surrounding floodplains, TSS levels increased and were positively associated with diarrheal cases (0- and 3-week lag). Populations living in this region utilized improved water sources, suggesting that hydrological variability and rapid water quality shifts in surface waters may compromise water treatment processes. Limitations include the potential influence of health beliefs and health seeking behaviors on data obtained through passive surveillance. CONCLUSIONS: In flood pulse river-floodplain systems, hydrology and water quality dynamics can be highly variable, potentially impacting conventional water treatment facilities and the production of safe drinking water. In Southern Africa, climate change is predicted to intensify hydrological variability and the frequency of extreme weather events, amplifying the public health threat of waterborne disease in surface-water-dependent populations. Water sector development should be prioritized with urgency, incorporating technologies that are robust to local environmental conditions and expected climate-driven impacts. In populations with high HIV burdens, expansion of diarrheal disease surveillance and intervention strategies may also be needed. As annual flood pulse processes are predominantly influenced by climate controls in distant regions, country-level data may be inadequate to refine predictions of climate-health interactions in these systems.

Advances in Evaluation of Chronic Diarrhea in Infants.

Diarrhea is common in infants (children less than 2 years of age), usually acute, and, if chronic, commonly caused by allergies and occasionally by infectious agents. Congenital diarrheas and enteropathies (CODEs) are rare causes of devastating chronic diarrhea in infants. Evaluation of CODEs is a lengthy process and infrequently leads to a clear diagnosis. However, genomic analyses and the development of model systems have increased our understanding of CODE pathogenesis. With these advances, a new diagnostic approach is needed. We propose a revised approach to determine causes of diarrhea in infants, including CODEs, based on stool analysis, histologic features, responses to dietary modifications, and genetic tests. After exclusion of common causes of diarrhea in infants, the evaluation proceeds through analyses of stool characteristics (watery, fatty, or bloody) and histologic features, such as the villus to crypt ratio in intestinal biopsies. Infants with CODEs resulting from defects in digestion, absorption, transport of nutrients and electrolytes, or enteroendocrine cell development or function have normal villi to crypt ratios; defects in enterocyte structure or immune-mediated conditions result in an abnormal villus to crypt ratios and morphology. Whole-exome and genome sequencing in the early stages of evaluation can reduce the time required for a definitive diagnosis of CODEs, or lead to identification of new variants associated with these enteropathies. The functional effects of gene mutations can be analyzed in model systems such as enteroids or induced pluripotent stem cells and are facilitated by recent advances in gene editing procedures. Characterization and investigation of new CODE disorders will improve management of patients and advance our understanding of epithelial cells and other cells in the intestinal mucosa.

Genetic and Structural Analysis of a SKIV2L Mutation Causing Tricho-hepato-enteric Syndrome.

BACKGROUND: Advances in genomics have facilitated the discovery of monogenic disorders in patients with unique gastro-intestinal phenotypes. Syndromic diarrhea, also called tricho-hepato-enteric (THE) syndrome, results from deleterious mutations in SKIV2L or TTC37 genes. The main features of this disorder are intractable diarrhea, abnormal hair, facial dysmorphism, immunodeficiency and liver disease. AIM: To report on a patient with THE syndrome and present the genetic analysis that facilitated diagnosis. METHODS: Whole-exome sequencing (WES) was performed in a 4-month-old female with history of congenital diarrhea and severe failure to thrive but without hair anomalies or dysmorphism. Since the parents were first-degree cousins, the analysis focused on an autosomal recessive model. Sanger sequencing was used to validate suspected variants. Mutated protein structure was modeled to assess the effect of the mutation on protein function. RESULTS: We identified an autosomal recessive C.1891G > A missense mutation (NM_006929) in SKIV2L gene that was previously described only in a compound heterozygous state as causing THE syndrome. The mutation was determined to be deleterious in multiple prediction models. Protein modeling suggested that the mutation has the potential to cause structural destabilization of SKIV2L, either through conformational changes, interference with the protein's packing, or changes at the protein's interface. CONCLUSIONS: THE syndrome can present with a broad range of clinical features in the neonatal period. WES is an important diagnostic tool in patients with congenital diarrhea and can facilitate diagnosis of various diseases presenting with atypical features.

Relationships among Common Illness Symptoms and the Protective Effect of Breastfeeding in Early Childhood in MAL-ED: An Eight-Country Cohort Study.

Children in low-income countries experience multiple illness symptoms in early childhood. Breastfeeding is protective against diarrhea and respiratory infections, and these illnesses are thought to be risk factors of one another, but these relationships have not been explored simultaneously. In the eight-site MAL-ED study, 1,731 infants were enrolled near birth and followed for 2 years. We collected symptoms and diet information through twice-weekly household visits. Poisson regression was used to determine if recent illness history was associated with incidence of diarrhea or acute lower respiratory infections (ALRI), accounting for exclusive breastfeeding. Recent diarrhea was associated with higher risk of incident diarrhea after the first 6 months of life (relative risk [RR] 1.10, 95% confidence interval [CI] 1.04, 1.16) and with higher risk of incident ALRI in the 3- to 5-month period (RR 1.23, 95% CI 1.03, 1.47). Fever was a consistent risk factor for both diarrhea and ALRI. Exclusive breastfeeding 0-6 months was protective against diarrhea (0-2 months: RR 0.39, 95% CI 0.32, 0.49; 3-5 months: RR 0.83, 95% CI 0.75, 0.93) and ALRI (3-5 months: RR 0.81, 95% CI 0.68, 0.98). Children with recent illness who were exclusively breastfed were half as likely as those not exclusively breastfed to experience diarrhea in the first 3 months of life. Recent illness was associated with greater risk of new illness, causing illnesses to cluster within children, indicating that specific illness-prevention programs may have benefits for preventing other childhood illnesses. The results also underscore the importance of exclusive breastfeeding in the first 6 months of life for disease prevention.

Novel Mutations in EPCAM Cause Congenital Tufting Enteropathy.

BACKGROUND AND AIMS: Congenital tufting enteropathy (CTE) is a rare autosomal recessive form of intractable diarrhea of infancy. Patients develop chronic diarrhea within days after birth, leading to severe malabsorption and significant mortality. CTE is characterized by subtotal villous atrophy with crypt hyperplasia. Typical features include abnormal villi in the intestinal epithelium and disorganization of surface enterocytes with focal crowding, resembling tufts. The pathogenesis of CTE remains poorly understood. CTE has been reported in Western populations, but until now had not been reported in China. The objective of this study was to identify the gene responsible for CTE in a Chinese individual. METHODS: A 13-year-old girl with suspected CTE, whose parents were both healthy, was evaluated in our clinic. Tissues were obtained by endoscopy and examined by electron microscopy. Genomic DNA, extracted from the peripheral blood of the child and parents, was subjected to whole-exome sequencing. After mutations in the gene encoding epithelial cell adhesion molecule (EPCAM) were identified, expression of EPCAM was examined by immunohistochemistry staining. RESULTS: Whole-exome sequencing revealed compound heterozygous mutations in EPCAM in the patient, with immunohistochemical analysis showing complete loss of EPCAM expression in the intestinal villi and crypts. CONCLUSIONS: We identified compound heterozygous mutations in EPCAM, with loss of EPCAM expression in duodenal enterocytes, in a patient with intractable diarrhea since infancy who was subsequently diagnosed with CTE. This is the first case of CTE to be reported in a Chinese patient.