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Variable clinical presentation of hypomorphic DCLRE1C deficiency from childhood to adulthood
Esra Hazar1,2, Mehmet Ali Karaselek1, Hasan Kapakli1
1Division of Pediatric Immunology and Allergy, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey.
Insights
Long-term follow-up of leaky severe combined immunodeficiency (SCID) patients with DCLRE1C mutations reveals variable clinical and immunological findings. A T helper 1 dominant response and increased T follicular helper cells may drive chronic inflammation and autoimmunity post-hematopoietic stem cell transplantation (HSCT).
Area of Science:
- Immunology
- Genetics
- Hematology
Background:
- Focuses on long-term follow-up of pediatric and adult patients with DCLRE1C hypomorphic mutations causing leaky severe combined immunodeficiency (SCID).
- Highlights the variability in clinical presentation and laboratory findings across different age groups.
Purpose of the Study:
- To report long-term outcomes in patients with DCLRE1C mutations and leaky SCID.
- To characterize clinical and immunological features before and after hematopoietic stem cell transplantation (HSCT).
Main Methods:
- Included 18 patients (13 children, 5 adults) aged 6-29 years with DCLRE1C hypomorphic mutations.
- Assessed clinical and immunological parameters including immunoglobulin levels, T/B cells, NK cells, Treg cells, and cytokines.
- Compared data pre- and post-HSCT with healthy controls.
Main Results:
- Common findings: recurrent infections (78%), skin issues (61%), autoimmune diseases (33%), malignancy (17%).
- Patients showed low IgA, B/T lymphopenia, decreased recent thymic emigrants, naive T/B cells, and CD56dimCD16+ cells.
- Elevated T follicular helper (TFH) and Th1 (IFN-γ) cell ratios observed, suggesting a Th1-dominant immune response.
Conclusions:
- Hypomorphic DCLRE1C mutations lead to diverse clinical and laboratory phenotypes.
- A Th1-dominant immune response, evidenced by increased IFN-γ and TFH cells, may contribute to chronic inflammation and autoimmunity.
- Further long-term follow-up post-HSCT is crucial for understanding disease pathophysiology.
Background:
In this study, we aimed to report long-term follow-up of our pediatric and adult patients with DCLRE1C (DNA cross-link repair 1C) hypomorphic mutation who were diagnosed leaky severe combined immunodeficiency (SCID).
Methods:
Eighteen patients (13 children and five adults), aged between 6 and 29 years were included. Clinical and immunological features, including immunoglobulin levels, T and B cells, natural killer cell subsets, regulator T (Treg) cell ratios/markers, and cytokines, were assessed before and after hematopoietic stem cell transplantation (HSCT) and compared with healthy controls.
Results:
Recurrent infections (78%) and skin manifestations (61%) such as granulomatous skin lesions, warts, and vitiligo were the most common clinical findings. Autoimmune diseases were observed in 33% and malignancy in 17%. Most patients had low serum IgA and B- and T-cell lymphopenia at the first admission. Recent thymic emigrants (RTE), Tnaive, Bnaive, CD56dimCD16+ cell ratios were significantly lower in the patients than in control; however, follicular helper T TFH and Th1 [interferon gamma (IFN-γ)] cell ratios were significantly higher than the control. Although, Treg ratio and its functional receptors tend to be high but not significant. Eleven patients (61.1%) were treated with HSCT. Median follow-up times of transplant patients was 56 (9-67) months.
Conclusion:
Patients with hypomorphic DCLRE1C mutations may present with variable clinical and laboratory findings at different ages. Our study showed a helper T (Th)1-dominant immune response before and after HSCT. Increased IFN-γ and TFH cells ratio could be a reason of chronic inflammation and autoimmunity developing before and after HSCT. Long-term follow-up of these patients after HSCT will help to better understand the disease and its pathophysiology.
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