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| [Paper Type: Novel mutation and VUS] AND [Author: Willett Pachul, Jessica] (4) | 26 Mar 2025 |
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- FREE ACCESSBackground: Eosinophilic gastrointestinal disease (EGID) is an umbrella term for a heterogeneous group of disorders affecting the GI tract. In contrast to the relatively common eosinophilic esophagitis (EoE), eosinophilic gastroenteritis (EGE) remains poorly understood in terms of both its pathophysiology and genetic etiology, while treatment options remain limited.Aim: To expand the genotypic spectrum of EGE and describe our long-term experience of treatment with ketotifen.Methods: Case report of a patient with EGE followed by our team for over 27 years.Results: Our patient was diagnosed with EGE at the age of 4 years, accompanied by multiple other atopic manifestations and serum eosinophilia. He was later diagnosed with a heterozygous variant in RUNX1, a gene implicated in multi-lineage hematopoiesis, inhibition of Th2 polarization and T regulatory cell function. The patient has experienced long-term symptom improvement while treated with the mast cell stabilizing H1 antihistamine, ketotifen, with substantial symptomatic worsening after this agent was briefly stopped.Conclusion: We expand the genotypic spectrum of EGID etiology to include mutations in RUNX1, and suggest ketotifen as a viable option for patients with treatment-refractory EGE.Statement of novelty: This case reports on a possible novel genetic cause of EGID and describes long-term successful clinical management with ketotifen.
- FREE ACCESS
- Laura Edith Abrego Fuentes,
- Jenny Garkaby,
- Jessica Willett Pachul,
- Abby Watts-Dickens,
- Meghan Fraser,
- Vy H.D. Kim, and
- Chaim M. Roifman
Background: Forkhead-box protein N1 (FOXN1) plays a critical role in the proper development and function of thymic epithelial cells, required for T cell ontogeny. Homozygous variants in the FOXN1 gene, encoding FOXN1, cause severe combined immunodeficiency (SCID), whereas heterozygous mutations are associated with variable presentations and over time, improving T cell function.Aim: To highlight the importance of broader genetic investigations to attain a definitive molecular diagnosis following abnormal newborn screening for SCID.Methods: Case report of a patient with immunodeficiency due to a novel de novo FOXN1 mutation.Results: The patient was identified following abnormal newborn screening for SCID in which T cell receptor excision circles were absent/very low. Initial immune investigations revealed severe T cell lymphopenia and poor lymphocyte function and she was diagnosed with T-B+NK+SCID. During work-up for hematopoietic stem cell transplantation, extensive genetic investigations identified a novel heterozygous mutation in FOXN1. A more conservative management approach was taken, and over the following months, the patient’s immune parameters improved.Conclusion: Newborn screening for SCID has facilitated the detection of SCID, as well as other T cell immunodeficiencies, before infectious complications and organ damage occur. Heterozygous mutations in FOXN1 are associated with more variable presentations including improving immune indices with age. Here, results of genetic investigations were essential for informing the management of this case.Statement of Novelty: We report a novel heterozygous mutation in FOXN1, presenting initially as T-B+NK+ SCID with gradual improvement of immune parameters over time. - FREE ACCESSBackground: Cytotoxic T lymphocyte-associated antigen-4 (CTLA4) haploinsufficiency is characterized by a variety of phenotypes, ranging from autoimmune disorders, enteropathy, fatal combined immunodeficiency, as well as lymphoproliferation and malignancy.Aim: To broaden the genotypic spectrum and clinical presentations of patients with CTLA4 variants.Methods: We evaluated a female patient with autoimmunity and lymphopenia. Immune workup and whole exome sequencing (WES) were performed.Results: The proband presented at 11 years of age with hypothyroidism and later developed Evans syndrome, alopecia, eczema, and lymphocytic interstitial pneumonia. Immune evaluation revealed T, B, and NK lymphopenia with normal humoral immunity. Following a negative genetic panel for autoimmune lymphoproliferative syndrome (ALPS), WES analysis identified a novel heterozygous intronic variant predicted in-silico to cause skipping of exon 2 of the CTLA4 gene.Conclusion: A novel heterozygous mutation in CTLA4 caused variable presentations of immune dysregulation, one of the hallmarks of CTLA4 haploinsufficiency.Statement of Novelty: We herein report a novel mutation in CTLA4 resulting in various features of autoimmunity.
- OPEN ACCESS
- Jenny Garkaby,
- Laura Edith Abrego Fuentes,
- Jessica Willett Pachul,
- Abby Watts-Dickens, and
- Meghan Fraser
Background: The T cell receptor (TCR)-α chain plays a key role in TCR structure and function. Biallelic mutations in TRAC, encoding the constant region of the TCR-α chain, obliterates TCR expression and results in immunodeficiency. TCR-α chain deficiency presents at infancy or childhood with repeated viral and bacterial infections, enlarged liver, spleen, and lymph nodes as well as autoimmune features and lymphoma (OMIM #615387).Aim: To broaden the genotypic and phenotypic spectrum of TCR-α chain deficiency.Methods: We present a case report of a patient with severe combined immunodeficiency (SCID) due to a novel autosomal recessive mutation in TRAC.Results: Our patient was identified at 13 days of life due to abnormal T cell receptor excision circle levels detected by newborn screening (NBS). Immune evaluation revealed profound lymphopenia, depressed responses to the mitogen PHA and a skewed T cell repertoire, all consistent with SCID. The patient was found to carry a novel homozygous mutation in the TRAC gene.Conclusion: A novel homozygous mutation in the TRAC gene caused profound T cell lymphopenia and aberrant in vitro mitogenic response, the hallmarks of SCID.Statement of Novelty: TCR-α chain deficiency is a rare and relatively new condition and not very well defined. We herein report a novel mutation in TRAC resulting in SCID.
