Familial Hemophagocytic Lymphohistiocytosis Type 5 in a Patient With Microvillous Inclusion Disease (MVID)
Bibliographic record
Abstract
Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically heterogeneous autosomal-recessive disorder characterized by a hyperstimulation of the immune system associated with a highly reduced capacity of natural killer cells and cytotoxic T lymphocytes to kill their targets. Mutations in different genes have been identified as the cause of FHL. FHL type 5 is due to mutations occurring in STXBP2, which encodes syntaxin binding protein 2, also known as Munc18-2, a protein that regulates membrane fusion events and, thus, vesicle exocytosis by controlling SNARE complex assembly via direct interaction with syntaxin 11. In addition to the immune system, Munc18-2 is localized at the apical surface of epithelial intestinal and renal cells. Interestingly, gastrointestinal symptoms, including diarrhea, have been described in patients with FHL type 5, but not in other types of FHL. We report the case of a male infant with ongoing neonatal diarrhea. Genetic analysis identified a mutation in Munc18-2, and, hence, a diagnosis of FLH type 5 was made. When he was 1 year old, he was subjected to a bone marrow transplant, which improved his condition. One year later, the patient returned with severe diarrhea. Light microscopy examination of a duodenal biopsy revealed villous atrophy without increase in intraepithelial lymphocytes. The PAS stain detected accumulation of PAS-positive granules within the apical cytoplasm of enterocytes. Ultrastructural analysis identified brush border abnormalities in enterocytes ranging from total loss to relatively normal appearance. In addition, numerous electron dense or lucent vesicles in the apical cytoplasm of enterocytes, as well as typical vesicular inclusions resembling phagolysosomes, and a few small intracytoplasmic microvillous inclusions, characteristic of MVID, were noted. Interestingly, these changes are seen in the late-onset form of MVID, which is caused by mutations of myosin 5B, another protein critical for intracellular vesicle trafficking. Thus, Munc18-2 might also be critical for the integrity of the intestinal epithelium, but the mechanism remains to be elucidated. This is a first report of FHL associated with MVID, both rare genetic disorders.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.002 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".