Loeys-Dietz syndrome with autoimmune polyendocrine syndrome type 4 and immune dysregulation associated with a heterozygous CD3G splice-site variant in a child: a case report.
- 1Department of Pediatrics and Child Health, Unit of Pediatric Endocrinology, Saint Paul Hospital Millennium Medical College, Addis Ababa, Ethiopia. [email protected].
- 2Department of Pediatrics, University of Cambridge and Cambridge University Hospital NHS Trust, Cambridge, UK.
Abstract
We report a 9-year-old boy presenting with early-onset autoimmune diabetes, chronic immune thrombocytopenia, celiac disease, recurrent severe infections beginning in infancy, glycogenic hepatopathy, and progressive aortic root dilatation. The clustering of autoimmune and infectious manifestations prompted genomic evaluation, which identified a heterozygous splice-site variant in CD3G (c.440-2 A > C), consistent with partial CD3γ deficiency, together with a pathogenic TGFBR2 variant (c.1570G > A; p.Asp524Asn) confirming Loeys-Dietz syndrome. The coexistence of impaired T-cell receptor signaling and disrupted transforming growth factor-β (TGF-β) pathway activity provides a mechanistic explanation for the patient's combined phenotype of immune dysregulation and syndromic vascular disease. Clinically, the constellation of type 1 diabetes, chronic immune thrombocytopenia, and celiac disease is consistent with autoimmune polyendocrine syndrome type 4 occurring in the context of monogenic immune regulatory defects. Although CD3γ deficiency is classically associated with biallelic variants, this case supports the emerging concept that heterozygous splice-site variants may contribute to immune dysregulation when present alongside additional pathogenic variants affecting immune tolerance pathways. This report highlights a previously unrecognized association between Loeys-Dietz syndrome and heterozygous CD3G-related immune dysregulation presenting as autoimmune polyendocrine syndrome type 4, underscoring the importance of genomic evaluation in children with clustered autoimmune disease and atypical infection susceptibility.
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BibTeX
@article{adinew2026loeysdietz,
title = {{Loeys-Dietz syndrome with autoimmune polyendocrine syndrome type 4 and immune dysregulation associated with a heterozygous CD3G splice-site variant in a child: a case report.}},
author = {Fikir M Adinew and M Loredana Marcovecchio},
journal = {BMC endocrine disorders},
year = {2026},
month = aug,
doi = {10.1186/s12902-026-02454-0},
url = {https://europepmc.org/article/MED/42972369},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Loeys-Dietz syndrome with autoimmune polyendocrine syndrome type 4 and immune dysregulation associated with a heterozygous CD3G splice-site variant in a child: a case report.
AU - Fikir M Adinew
AU - M Loredana Marcovecchio
PY - 2026
DA - 2026/08/05
JO - BMC endocrine disorders
DO - 10.1186/s12902-026-02454-0
UR - https://europepmc.org/article/MED/42972369
AB - We report a 9-year-old boy presenting with early-onset autoimmune diabetes, chronic immune thrombocytopenia, celiac disease, recurrent severe infections beginning in infancy, glycogenic hepatopathy, and progressive aortic root dilatation. The clustering of autoimmune and infectious manifestations prompted genomic evaluation, which identified a heterozygous splice-site variant in CD3G (c.440-2 A > C), consistent with partial CD3γ deficiency, together with a pathogenic TGFBR2 variant (c.1570G > A; p.Asp524Asn) confirming Loeys-Dietz syndrome. The coexistence of impaired T-cell receptor signaling and disrupted transforming growth factor-β (TGF-β) pathway activity provides a mechanistic explanation for the patient's combined phenotype of immune dysregulation and syndromic vascular disease. Clinically, the constellation of type 1 diabetes, chronic immune thrombocytopenia, and celiac disease is consistent with autoimmune polyendocrine syndrome type 4 occurring in the context of monogenic immune regulatory defects. Although CD3γ deficiency is classically associated with biallelic variants, this case supports the emerging concept that heterozygous splice-site variants may contribute to immune dysregulation when present alongside additional pathogenic variants affecting immune tolerance pathways. This report highlights a previously unrecognized association between Loeys-Dietz syndrome and heterozygous CD3G-related immune dysregulation presenting as autoimmune polyendocrine syndrome type 4, underscoring the importance of genomic evaluation in children with clustered autoimmune disease and atypical infection susceptibility.
SN - 1472-6823
ER -