Phenotypic and genetic characterization of heterozygous <i>FOXN1</i> variants: a case series of mild immunodeficiency
Bibliographic record
Abstract
Background: FOXN1 belongs to the Foxhead-box (FOX) family of transcription factors and is fundamental for the successful development of T cells in the thymus. Homozygous pathogenic variants in the FOXN1 gene are associated with a severe combined immunodeficiency (SCID) phenotype. In contrast, individuals carrying a heterozygous single pathogenic variant in FOXN1 demonstrate a less severe phenotype. Patients described thus far can present with frequent mild respiratory infections and associated T cell lymphopenia that has been shown to improve with age. We present three patients with heterozygous variants in FOXN1 presenting with a mild clinical phenotype. Methods: Informed consent was obtained from patients and families. Case data was compiled retrospectively from the patients’ medical charts. Genetic testing used an augmented exome slice of 251 genes implicated in inborn errors of immunity, with Sanger backfill of select genes. Case presentation: Probands P1 and P2 are two unrelated pediatric patients identified by a positive newborn screen for SCID. P3 is the father of P2. All were found to have heterozygous pathogenic variants in FOXN1. In P1 and P2, laboratory investigations revealed T cell lymphopenia on initial bloodwork. Lymphopenia improved with age. A surveillance approach was taken to manage both pediatric patients, based on local experience with similar presentations, and both have done well thus far. Aside from a typical number of minor infections including common upper respiratory tract illnesses and otitis media, neither child had infections requiring hospitalizations or IV antibiotics. Additionally, P1 and P2 tolerated live viral vaccines. P3 had a history of 1 severe dental infection but had otherwise been well prior to diagnosis, and since. Conclusion: With the increasing implementation of newborn screening, patients with heterozygous pathogenic variants in FOXN1 are increasingly identified. No clear care pathway has been established. Our cases add to the growing body of literature in presenting a cohort of patients with heterozygous pathogenic FOXN1 variants whose phenotype indicates mild, self-resolving infections despite T cell lymphopenia. It will be important to identify and follow these patients longitudinally to consider recommendation of a surveillance approach if appropriate, and to provide guidance to affected families regarding the trajectory of this condition. Statement of novelty: Heterozygous FOXN1 deficiency is currently an insufficiently understood condition, and its optimal management continues to be unclear. We present 2 case reports of children for whom a surveillance approach was taken successfully. Additionally, we describe a healthy adult who was found to have a heterozygous variant later in life.
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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 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".