Dual novel variants in CD40 leading to hyper IgM syndrome: a case report of a school-aged female with new-onset recurrent pneumonia
Why this work is in the frame
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Bibliographic record
Abstract
Introduction: Hyper IgM (HIGM) syndrome is an inborn error of immunity (IEI) that occurs due to defects in immunoglobulin class switch recombination (Ig-CSR). HIGM syndrome typically presents with recurrent infections in early childhood, and is often characterized on investigation with decreased IgG, IgA, and IgE titres, alongside normal or elevated IgM. A common cause of HIGM syndrome is a disruption to the CD40-CD40 ligand (CD40L) interaction that triggers Ig-CSR, of which variants in CD40 are much rarer than those in CD40L. We present a case of an 11-year-old female with HIGM syndrome caused by two novel variants of in the CD40 gene. Aim: To describe a case report of an eleven-year-old female with HIGM syndrome presenting with recurrent pneumonia. Methods: Data was collected retrospectively from the patient’s medical records. Laboratory investigations included quantitative immunoglobulins, quantitative B and T cell subsets, genetic testing using a primary immunodeficiency panel, and a functional assay for CD40 expression. Results: The proband is an 11-year-old female, who presented with recurrent pneumonia, otitis, and septic arthritis. Investigations revealed neutropenia, low IgA, elevated IgM and normal IgG, along with absent vaccine responses. She was identified to harbour two novel variants in CD40: an intronic variant c.52-13A>G p.(?) and a missense variant c.466T>C p.(Ser156Pro). Functional assay indicated low expression of CD40 compared to healthy control, confirming the diagnosis of CD40 deficiency. Conclusion: Class switch defects, such as CD40 deficiency, are rare but significant diagnoses within the spectrum of IEI. This case demonstrates that despite the absence of some clinical red flags for immunodeficiency in infancy, IEIs remain an important consideration in pediatric patients regardless of age. Increasing clinical awareness of IEI will lead to earlier diagnoses, initiation of appropriate treatment, and prevention of potential complications. Statement of novelty: We describe a patient with a late presentation of hyper IgM syndrome due to two novel variants in the CD40 gene, thus expanding the spectrum of CD40 gene variants.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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