Early-onset type 1 diabetes mellitus in a child with a pathogenic CTLA4 variant complicated by generalized lipodystrophy and severe insulin resistance: a case report and literature review.
The co-occurrence of early-onset type 1 diabetes mellitus (T1DM), acquired generalized lipodystrophy (AGL), and severe insulin resistance (SIR) is extremely rare, poses significant therapeutic challenges and no cases associated with pathogenic Cytotoxic T-lymphocyte-associated 4 (CTLA4) variants have been previously documented.
We performed genetic testing, flow cytometric immunophenotyping, leptin measurement and a 4.5-year clinical follow-up in a 3-year-3-month-old boy with early-onset T1DM, insulin allergy following initial insulin therapy, progressive lipodystrophy, SIR and mild hepatic dysfunction. We additionally conducted a systematic literature review to summarize CTLA4 variant-related autoimmune endocrine disorders and fat metabolism abnormalities. Pathological biopsy of subcutaneous adipose tissue revealed scattered lymphocytes and histiocytes infiltrating the fat septa and perivascular areas. A heterozygous pathogenic c.151C>T (p.Arg51*) variant in the CTLA4 gene was identified by whole-exome sequencing (WES) analysis. His father and sister carried the same variant with incomplete penetrance. The patient showed markedly reduced CTLA4 expression on regulatory T cells and undetectable serum leptin. Treatment with abatacept normalized liver function but did not improve glycemic control or insulin resistance. During the follow-up, the patient's growth consistently exceeded the 97th percentile for age and gender.
This report established the first association between a pathogenic CTLA4 variant and AGL, which expands the known clinical phenotypic spectrum of CTLA4-related immune dysregulation disorders. CTLA4 genetic testing should be considered in patients presenting with early-onset T1DM and unexplained lipodystrophy to enable early diagnosis and guide personalized management.
We performed genetic testing, flow cytometric immunophenotyping, leptin measurement and a 4.5-year clinical follow-up in a 3-year-3-month-old boy with early-onset T1DM, insulin allergy following initial insulin therapy, progressive lipodystrophy, SIR and mild hepatic dysfunction. We additionally conducted a systematic literature review to summarize CTLA4 variant-related autoimmune endocrine disorders and fat metabolism abnormalities. Pathological biopsy of subcutaneous adipose tissue revealed scattered lymphocytes and histiocytes infiltrating the fat septa and perivascular areas. A heterozygous pathogenic c.151C>T (p.Arg51*) variant in the CTLA4 gene was identified by whole-exome sequencing (WES) analysis. His father and sister carried the same variant with incomplete penetrance. The patient showed markedly reduced CTLA4 expression on regulatory T cells and undetectable serum leptin. Treatment with abatacept normalized liver function but did not improve glycemic control or insulin resistance. During the follow-up, the patient's growth consistently exceeded the 97th percentile for age and gender.
This report established the first association between a pathogenic CTLA4 variant and AGL, which expands the known clinical phenotypic spectrum of CTLA4-related immune dysregulation disorders. CTLA4 genetic testing should be considered in patients presenting with early-onset T1DM and unexplained lipodystrophy to enable early diagnosis and guide personalized management.
Authors
Ding Ding, Li Li, Zhang Zhang, Gao Gao, Li Li, Ying Ying, Yao Yao, Yu Yu, Wang Wang
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