Advances in Evaluation of Chronic Diarrhea in Infants
Jay R Thiagarajah1, Daniel S Kamin1, Sari Acra2
1Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Insights
A new diagnostic approach for infant diarrhea, including rare congenital diarrheas and enteropathies (CODEs), combines stool analysis, histology, diet response, and genetic testing for faster diagnosis.
Area of Science:
- Pediatric Gastroenterology
- Genetics
- Molecular Biology
Background:
- Chronic diarrhea in infants, particularly Congenital Diarrheas and Enteropathies (CODEs), presents a diagnostic challenge.
- Current evaluation methods for CODEs are lengthy and often inconclusive.
- Advances in genomics and model systems offer new insights into CODE pathogenesis.
Purpose of the Study:
- To propose a revised, integrated diagnostic approach for infant diarrhea, including rare CODEs.
- To expedite the diagnosis of infant diarrheal disorders through a multi-faceted strategy.
- To leverage genomic and functional analyses for identifying novel CODEs.
Main Methods:
- Exclusion of common diarrhea causes followed by stool analysis (watery, fatty, bloody).
- Histologic examination of intestinal biopsies, focusing on villus to crypt ratio and morphology.
- Integration of dietary modification responses and genetic testing, including whole-exome/genome sequencing.
- Utilizing model systems (enteroids, iPSCs) and gene editing for functional variant analysis.
Main Results:
- The proposed approach categorizes CODEs based on villus to crypt ratio and underlying defects (e.g., nutrient transport vs. enterocyte structure).
- Early genomic sequencing can significantly shorten diagnostic timelines for CODEs.
- Identification of new genetic variants associated with infant enteropathies is facilitated.
Conclusions:
- A revised diagnostic strategy incorporating genetic and functional analyses improves infant diarrhea evaluation.
- This approach enhances the timely diagnosis and understanding of rare Congenital Diarrheas and Enteropathies.
- Further characterization of CODE disorders will advance intestinal mucosal biology and patient management.
Abstract:
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.
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