Congenital Diarrheal Diseases.

Early diagnosis of diarrhea is critical to prevent disease progression. Diarrhea in newborns can be congenital or acquired; acquired diarrheas are the major cause in infants. Congenital diarrheal diseases are rare and include defects in digestion, absorption, and transport of nutrients, and electrolytes; disorders of enterocyte differentiation and polarization; defects of enteroendocrine cell differentiation; dysregulation of the intestinal immune response; and dysfunction of the immune system. This review discusses the clinical approach that may help in early identification and management of different congenital diarrheal diseases.

Intestinal Failure: A Description of the Problem and Recent Therapeutic Advances.

Pediatric intestinal failure occurs when gut function is insufficient to meet the nutrient and hydration needs of the growing child. The commonest cause is short bowel syndrome with maldigestion and malabsorption following massive bowel loss. The remnant bowel adapts during the process of intestinal rehabilitation. Management promotes the achievement of enteral autonomy while mitigating the risk of comorbid disease. The future of care is likely to see expansion of pharmacologic methods for augmenting bowel adaptation, tissue engineering techniques enabling immune suppression-free autologous bowel transplant, and the development of electronic health record tools for efficient, collaborative study and care improvement.

Congenital Diarrheal Syndromes.

Congenital diarrheal disorders are heterogeneous conditions characterized by diarrhea with onset in the first years of life. They range from simple temporary conditions, such as cow's milk protein intolerance to irreversible complications, such as microvillous inclusion disease with significant morbidity and mortality. Advances in genomic medicine have improved our understanding of these disorders, leading to an ever-increasing list of identified causative genes. The diagnostic approach to these conditions consists of establishing the presence of diarrhea by detailed review of the history, followed by characterizing the composition of the diarrhea, the response to fasting, and with further specialized testing.

A Rare Cause of Intractable Diarrhea of Infancy.

Intractable watery diarrhea presenting in the neonatal period is a relatively uncommon condition. Congenital disorders of malabsorption are among the major causes of prolonged watery diarrhea. This is the case report of a 3-month male infant born to consanguineous parents, who presented with intractable diarrhea since birth. He was failing to thrive and wasted. Persistent diarrhea lead to prolonged hospitalisation and recurrent hypernatremic dehydration. Relevant investigations clinched the diagnosis of ''congenital glucose galactose malabsorption (CGGM)''. The astute clinician should have a high index of suspicion regarding such rare causes of diarrhea in early infancy, as an appropriate rational diagnosis can lead to life-saving treatment as depicted in this case report.

A New Case of Congenital Malabsorptive Diarrhea and Diabetes Secondary to Mutant Neurogenin-3.

Congenital diarrheal disorders are a group of rare enteropathies that often present with life-threatening diarrhea in the first weeks of life. Enteric anendocrinosis, characterized by a lack of intestinal enteroendocrine cells due to recessively inherited mutations in the Neurogenin-3 (NEUROG3) gene, has been described as a cause of congenital malabsorptive diarrhea. Diabetes mellitus also is typically associated with NEUROG3 mutations, be it early onset or a later presentation. Here we report a case of a 16-year-old male patient with severe malabsorptive diarrhea from birth, who was parenteral nutrition dependent and who developed diabetes mellitus at 11 years old. To the best of our knowledge, only 9 cases of recessively inherited NEUROG3 mutations have been reported in the literature to date. Our patient presents with several remarkable differences compared with previously published cases. This report can contribute by deepening our knowledge on new aspects of such an extremely rare disease.

Congenital Glucose-Galactose Malabsorption: A Case Report.

Congenital glucose-galactose malabsorption (CGGM) is a rare cause of intractable infantile diarrhea, with only a few hundred cases recognized worldwide. This life-threatening disorder must be considered in the differential diagnosis of an infant who presents with diarrhea and dehydration that fails to respond to standard therapy. The clinical and diagnostic course of an infant with recurrent episodes of watery diarrhea and hypernatremic dehydration found to be homozygous for a rare variant in the SLC5A1 gene, c.187C>T (p.R63X) is described.

DGAT1 mutation is linked to a congenital diarrheal disorder.

Congenital diarrheal disorders (CDDs) are a collection of rare, heterogeneous enteropathies with early onset and often severe outcomes. Here, we report a family of Ashkenazi Jewish descent, with 2 out of 3 children affected by CDD. Both affected children presented 3 days after birth with severe, intractable diarrhea. One child died from complications at age 17 months. The second child showed marked improvement, with resolution of most symptoms at 10 to 12 months of age. Using exome sequencing, we identified a rare splice site mutation in the DGAT1 gene and found that both affected children were homozygous carriers. Molecular analysis of the mutant allele indicated a total loss of function, with no detectable DGAT1 protein or activity produced. The precise cause of diarrhea is unknown, but we speculate that it relates to abnormal fat absorption and buildup of DGAT substrates in the intestinal mucosa. Our results identify DGAT1 loss-of-function mutations as a rare cause of CDDs. These findings prompt concern for DGAT1 inhibition in humans, which is being assessed for treating metabolic and other diseases.

[Congenital diarrhoea]. / Biegunka wrodzona.

Congenital diarrhoea of heterogenic etiology is a rare cause of chronic diarrhoea. Characteristic features are: onset in the first weeks of life, life-threatening severe dehydratation and electrolyte disorders leading to a necessity of long-term parenteral nutrition. The clinical onset may be delayed and the degree of diarrhoea may be modest, making the diagnosis difficult. The main causes of congenital diarrhoea such as intestine electrolytes, carbohydrates, lipid and protein transport disorders and congenital enzymatic deficiencies, enterocyte polarization disorders, hormonal, immunological, metabolic, genetic and congenital anatomic disorders are presented in the paper. Some of them, such as: microvillus inclusion disease, tufting enteropathy, intestinal anedocrynosis, IPEX syndrome (immunodysregulation polyendocrinopathy enteropathy X-linked syndrome) have been described recently. One of the basic investigations, when congenital diarrhea is suspected, is general examination of the stool, its electrolyte concentration and serum electrolytes and blood gas analysis. Often, small bowel biopsy with histological examination (with the use of electronic microscopy and PAS staining) is indicated. In some cases molecular examination is possible and indicated. In differential diagnosis other, more frequent causes of chronic diarrhea of infancy, have to be excluded. In most of the cases of congenital diarrhoea there is no casual treatment available - usually long-term parenteral nutrition is necessary.

Clorhidrorrea congénita: primer reporte en Cuba / Congenital chlorhydria: first report in Cuba

En el presente trabajo se exponen los antecedentes prenatales, perinatales y posnatales de un lactante de 6 meses de edad, del sexo masculino, con clorhidrorrea congénita, así como el cuadro clínico, diagnóstico y tratamiento utilizado. Un elemento significativo lo constituyó la expulsión anal de abundante líquido no meconial desde las primeras horas de nacido, así como alcalosis metabólica grave y la presencia de desnutrición rápidamente progresiva. En los exámenes complementarios se constató hipocloremia de un 50 por ciento con respecto a las cifras de referencia y un pH sanguíneo mayor de 7,50. El diagnóstico confirmatorio se obtuvo al comprobar concentraciones de cloro en heces fecales superiores a las de la suma de sodio y potasio. Se proponen indicadores diagnósticos prenatales entre los que tienen gran valor la consanguinidad, el polihidramnios y los resultados del ultrasonido en el tercer trimestre del embarazo. El diagnóstico precoz permitió establecer el tratamiento y evitó el frecuente desenlace fatal. Es el primer caso de esta enfermedad que se informa en el país(AU)

In present paper are showed the prenatal, perinatal and postnatal backgrounds from a male breast-fed baby aged 6 months presenting with congenital chlorhydria, as well as the clinical picture, diagnosis and treatment applied. A significant element was the anal expulsion of non-meconium abundant fluid from the first hours of born, as well as a severe metabolic alkalosis and the presence of a quickly progressive malnutrition. In complementary examinations was confirmed a 50 percent hypochloremia regarding the reference figures and a blood pH over 7,50. Confirmatory diagnosis was achieved verifying the chlorine concentrations in feces higher to that of the sum of sodium and potassium. Prenatal diagnostic indicators are proposed those with higher value including the consanguinity, polyhydramnios and the US results during the third trimester of pregnancy. Early diagnosis allowed us to establish the treatment and to prevent a fatal outcome. This is the firs case of this entity reported in our country(AU)

Identification of EpCAM as the gene for congenital tufting enteropathy.

BACKGROUND & AIMS: Congenital tufting enteropathy (CTE) is a rare autosomal recessive diarrheal disorder presenting in the neonatal period. CTE is characterized by intestinal epithelial cell dysplasia leading to severe malabsorption and significant morbidity and mortality. The pathogenesis and genetics of this disorder are not well understood. The objective of this study was to identify the gene responsible for CTE. METHODS: A family with 2 children affected with CTE was identified. The affected children are double second cousins providing significant statistical power for linkage. Using Affymetrix 50K single nucleotide polymorphism (SNP) chips, genotyping was performed on only 2 patients and 1 unaffected sibling. Direct DNA sequencing of candidate genes, reverse-transcription polymerase chain reaction, immunohistochemistry, and Western blotting were performed on specimens from patients and controls. RESULTS: SNP homozygosity mapping identified a unique 6.5-Mbp haplotype of homozygous SNPs on chromosome 2p21 where approximately 40 genes are located. Direct sequencing of genes in this region revealed homozygous G>A substitution at the donor splice site of exon 4 in epithelial cell adhesion molecule (EpCAM) of affected patients. Reverse-transcription polymerase chain reaction of duodenal tissue demonstrated a novel alternative splice form with deletion of exon 4 in affected patients. Immunohistochemistry and Western blot of patient intestinal tissue revealed decreased expression of EpCAM. Direct sequencing of EpCAM from 2 additional unrelated patients revealed novel mutations in the gene. CONCLUSIONS: Mutations in the gene for EpCAM are responsible for CTE. This information will be used to gain further insight into the molecular mechanisms of this disease.

Microvillous inclusion disease: ultrastructural variability.

Microvillous inclusion disease (MVID) is a congenital, usually neonatal, autosomal recessive condition manifested by severe, prolonged secretory diarrhea. Intestinal biopsies reveal extensive microvilli abnormalities, typical inclusions and vesicles mainly of the apical-luminal enterocytes and colonocytes. Although diagnosis can be suspected by special stains of the mucosa (PAS, CD10), the definitive diagnosis, recommended in view of potential intestinal transplantation, requires electron microscopy. In view of the marked variability of ultrastructural changes, extensive illustration is considered valuable for diagnosis. While the pathogenesis is still unknown, a number of images illustrate the suspected "arrested-trafficking" hypothesis of microvillous abnormalities. Others micrographs support the "engulfing" mechanism of inclusion formation. The electron micrographs should help ultrastructural diagnosis in this heterogeneous disease and can confirm diagnosis even in the absence of the typical inclusions.

Microvillous inclusion disease (microvillous atrophy).

Microvillous inclusion disease (MVID) or microvillous atrophy is a congenital disorder of the intestinal epithelial cells that presents with persistent life-threatening watery diarrhea and is characterized by morphological enterocyte abnormalities. MVID manifests either in the first days of life (early-onset form) or in the first two months (late-onset form) of life. MVID is a very rare disorder of unknown origin, probably transmitted as an autosomal recessive trait. To date, no prevalence data are available. Ultrastructural analyses reveal: 1) a partial to total atrophy of microvilli on mature enterocytes with apical accumulation of numerous secretory granules in immature enterocytes; 2) the highly characteristic inclusion bodies containing rudimentary or fully differentiated microvilli in mature enterocytes. Light microscopy shows accumulation of PAS-positive granules at the apical pole of immature enterocytes, together with atrophic band indicating microvillus atrophy and, in parallel, an intracellular PAS or CD10 positive line (marking the microvillous inclusion bodies seen on electron microscopy). Intestinal failure secondary to diarrhea is definitive. To date, no curative therapy exists and children with MVID are totally dependent on parenteral nutrition. Long-term outcome is generally poor, due to metabolic decompensation, repeated states of dehydration, infectious and liver complications related to the parenteral nutrition. As MVID is a very rare disorder, which is extremely difficult to diagnose and manage, children with MVID should be transferred to specialized pediatric gastro-intestinal centers, if possible, a center equipped to perform small bowel transplantation. Early small bowel transplantation resulting in intestinal autonomy gives new hope for disease management and outcome.

Microvillus inclusion disease: progressive mucosal pathology. A scanning and transmission electron microscopic study, and thoughts about possible pathogenesis.

An infant of African-American descent presented in the immediate newborn period with secretory diarrhea, the cause of which turned out to be microvillus inclusion disease (MID). Small intestinal mucosal biopsies at 6 weeks of age were diagnostic for MID by electron microscopy and repeat biopsies from the small intestine at 15 months demonstrated the seeming relentless progression of this disorder, when a normal structure and organization of small intestinal mucosa was no longer recognizable. Since the child could not tolerate any form of enteral nutrition, a small intestinal transplant was contemplated, but could not be done. The patient did not survive the consequences of an overwhelming sepsis, which resulted in multi-organ failure.

[Congenital chloride diarrhea]. / Clorhidrorrea congénita.

Congenital chloride diarrhea (CCD) is a rare hereditary disease, with a prenatal onset, secondary to a deficit in the intestinal chloride transport. In the present study, we describe the clinical characteristics of three patients with congenital watery diarrhea, two of them females, aged between 9 and 14 months at the first visit. All patients presented perinatal antecedents of polyhydramnios and prematurity, watery stools since birth and growth failure. Metabolic alkalosis, hypokalemia and hypochloremia were found. Stool ionogram with elevated doses of chloride, exceeding both sodium and potassium, confirmed the diagnosis of CCD. Substitute treatment with sodium and potassium chloride was started with good results. CCD should be considered as a differential diagnosis to congenital watery diarrhea, since early diagnosis and appropriate treatment are mandatory for the normal development of the child, avoiding severe complications such as neurological sequelae and even death.

Clorhidrorrea congénita / Congenital chloride diarrhea

Congenital chloride diarrhea (CCD) is a rare hereditary disease, with a prenatal onset, secondary to a deficit in the intestinal chloride transport. In the present study, we describe the clinical characteristics of three patients with congenital watery diarrhea, two of them females, aged between 9 and 14 months at the first visit. All patients presented perinatal antecedents of polyhydramnios and prematurity, watery stools since birth and growth failure. Metabolic alkalosis, hypokalemia and hypochloremia were found. Stool ionogram with elevated doses of chloride, exceeding both sodium and potassium, confirmed the diagnosis of CCD. Substitute treatment with sodium and potassium chloride was started with good results. CCD should be considered as a differential diagnosis to congenital watery diarrhea, since early diagnosis and appropriate treatment are mandatory for the normal development of the child, avoiding severe complications such as neurological sequelae and even death.(AU)

La clorhidrorrea congénita (CHC) es una enfermedad hereditaria rara, de comienzo prenatal secundaria aun defecto en el transporte intestinal de cloro. En este trabajo describimos las características clínicas de tres pacientes con diarrea acuosa congénita, dos desexo femenino, con edades comprendidas entre 9 y 14meses al momento de la consulta. Todos presentaban antecedentes perinatales de polihidramnios y prematurez,deposiciones líquidas desde el nacimiento y mal progreso ponderal. Se comprobó alcalosis metabólica,hipokalemia e hipocloremia. El ionograma en materia fecal, con dosajes de cloro elevado que superaban la sumade sodio y potasio, permitió confirmar el diagnóstico de CHC. Se instituyó tratamiento sustitutivo con cloruro de sodio y de potasio, con evolución favorable. Es de suma importancia tener en cuenta la CHC dentro de los diagnósticos diferenciales de diarrea acuosa congénita, ya que el diagnóstico precoz y el tratamiento adecuado permiten un desarrollo normal, evitandocomplicaciones graves, como secuelas neurológicas e incluso la muerte.(AU)

Clorhidrorrea congénita / Congenital chloride diarrhea

Congenital chloride diarrhea (CCD) is a rare hereditary disease, with a prenatal onset, secondary to a deficit in the intestinal chloride transport. In the present study, we describe the clinical characteristics of three patients with congenital watery diarrhea, two of them females, aged between 9 and 14 months at the first visit. All patients presented perinatal antecedents of polyhydramnios and prematurity, watery stools since birth and growth failure. Metabolic alkalosis, hypokalemia and hypochloremia were found. Stool ionogram with elevated doses of chloride, exceeding both sodium and potassium, confirmed the diagnosis of CCD. Substitute treatment with sodium and potassium chloride was started with good results. CCD should be considered as a differential diagnosis to congenital watery diarrhea, since early diagnosis and appropriate treatment are mandatory for the normal development of the child, avoiding severe complications such as neurological sequelae and even death.

La clorhidrorrea congénita (CHC) es una enfermedad hereditaria rara, de comienzo prenatal secundaria aun defecto en el transporte intestinal de cloro. En este trabajo describimos las características clínicas de tres pacientes con diarrea acuosa congénita, dos desexo femenino, con edades comprendidas entre 9 y 14meses al momento de la consulta. Todos presentaban antecedentes perinatales de polihidramnios y prematurez,deposiciones líquidas desde el nacimiento y mal progreso ponderal. Se comprobó alcalosis metabólica,hipokalemia e hipocloremia. El ionograma en materia fecal, con dosajes de cloro elevado que superaban la sumade sodio y potasio, permitió confirmar el diagnóstico de CHC. Se instituyó tratamiento sustitutivo con cloruro de sodio y de potasio, con evolución favorable. Es de suma importancia tener en cuenta la CHC dentro de los diagnósticos diferenciales de diarrea acuosa congénita, ya que el diagnóstico precoz y el tratamiento adecuado permiten un desarrollo normal, evitandocomplicaciones graves, como secuelas neurológicas e incluso la muerte.

Congenital sodium diarrhea in a neonate presenting as acute renal failure.

Congenital sodium diarrhea is a rare cause of secretory diarrhea due to a defect in the sodium/proton exchanger that results in decreased sodium absorption and increased excretion in stools. We report a pre-term baby boy with a birth weight of 1.4 kg who was referred because of rapidly rising serum urea and creatinine. The initially reported high urine output was later found to be severe watery diarrhea with severe oliguria and acute renal failure. Associated findings were normal anion gap metabolic acidosis with hyponatremia that required > 50 mmol/kg of sodium per day for correction and about 300 ml/kg per day of replacement fluid to correct fluid and electrolyte abnormalities. The patient continues to do well 5 months after diagnosis.