Identification of novel compound heterozygous <i>LRBA</i> mutations associated with recurrent hemophagocytic lymphohistiocytosis and CNS manifestations
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Bibliographic record
Abstract
Background: Lipopolysaccharide-responsive beige-like anchor (LRBA) is an intracellular protein that regulates the recycling of cytotoxic T lymphocyte-associated protein 4 (CTLA4), an immune checkpoint molecule which prevents ongoing activation of T cells. Deficiency of LRBA results in increased trafficking and degradation of CTLA4, and consequently, uncontrolled T cell responses. The phenotypic spectrum of LRBA deficiency arising from biallelic loss-of-function typically includes recurrent infections, autoimmunity, lymphoproliferation, chronic diarrhea, hypogammaglobulinemia, and cytopenia. Aim: To report an atypical presentation of LRBA deficiency arising from a set of compound heterozygous LRBA variants, encompassing recurrent hemophagocytic lymphocytosis (HLH) and neurological manifestations. Methods: Clinical data was gathered through retrospective chart review. Expanded genetic analysis including whole exome sequencing was performed. Results: Our patient initially presented at age 15 months with fever, seizures, and encephalopathy. HLH-work-up showed bicytopenia, elevated ferritin and triglyceride, and low fibrinogen, however, he did not yet meet the diagnostic criteria for HLH. MRI brain and EEG at diagnosis was suggestive of acute necrotizing encephalopathy of childhood. He responded to pulsed IV methylprednisolone treatment with minimal residual neurological deficit on follow-up. At 36 months of age, he had a repeat presentation and rapidly deteriorated. He developed severe encephalopathy with fixed dilated pupils. Whole exome sequencing revealed a set of compound heterozygous missense variants in the LRBA gene, a novel c.2206A>T (p.R736W) and c.5989C>T (p.R1997C) variant. Conclusion: Compound heterozygous mutations in the LRBA gene caused an atypical presentation of recurrent HLH with central nervous system (CNS) manifestations in our patient. Statement of Novelty: We herein report a novel set of compound heterozygous mutations in LRBA with atypical presentation of recurrent HLH with CNS manifestations, thus expanding the known phenotypic spectrum of LRBA deficiency.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 it