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<p>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 <i>CD3G (c.440–2&#xa0;A &gt; C)</i>, consistent with partial CD3γ deficiency, together with a pathogenic <i>TGFBR2</i> variant (<i>c.1570G &gt; A; p.Asp524Asn</i>) 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 <i>CD3</i>γ 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 <i>CD3G</i>-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.</p>

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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

  • 期刊论文

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  • 发表日期：

    2026年8月5日

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  • Fikir M. Adinew,
  • M. Loredana Marcovecchio

摘要

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.