Case report: type 1 diabetes in monozygotic quadruplets

Abstract

Type 1 diabetes (T1D) is an autoimmune disease characterized by the lack of insulin due to an autoimmune destruction of pancreatic beta cells. Here, we report a unique case of a family with naturally conceived quadruplets in which T1D was diagnosed in two quadruplets simultaneously. At the same time, the third quadruplet was diagnosed with the pre-diabetic stage. Remarkably, all four quadruplets were positive for anti-islet cell antibodies, GAD65 and IA-A2. Monozygotic status of the quadruplets was confirmed by testing 14 different short tandem repeat polymorphisms. Serological examination confirmed that all quadruplets and their father suffered from a recent enteroviral infection of EV68-71 serotype. To assess the nature of the molecular pathological processes contributing to the development of diabetes, immunocompetent cells isolated from all family members were characterized by gene expression arrays, immune-cell enumerations and cytokine-production assays. The microarray data provided evidence that viral infection, and IL-27 and IL-9 cytokine signalling contributed to the onset of T1D in two of the quadruplets. The propensity of stimulated immunocompetent cells from non-diabetic members of the family to secrete high level of IFN-α further corroborates this conclusion. The number of T regulatory cells as well as plasmacytoid and/or myeloid dendritic cells was found diminished in all family members. Thus, this unique family is a prime example for the support of the so-called 'fertile-field' hypothesis proposing that genetic predisposition to anti-islet autoimmunity is 'fertilized' and precipitated by a viral infection leading to a fully blown T1D.

Figure 1

The family tree with indicated HLA DQ types. The quadruplets (A–D) are genetically monozygotic and DQ homozygous. The quadruplets A and B had simultaneous presentation of T1D just 1 month after an apparent enteroviral infection. The quadruplet C is in the pre-diabetic phase. The quadruplet D and an older sister (S) are diabetes free. All four quadruplets (A–D) produce anti-islet cell antibodies to GAD65 and IA-A2 autoantigens. HLA DQ types of mother (M) and Father (F) are also indicated.

Figure 2

Microarray heat map of genes belonging to 10 most differentially regulated pathways between the diabetic and the non-diabetic quadruplets. A simplified view with averaged gene expression values of diabetic (A and B) and non-diabetic sisters (C and D) is presented. Red and blue indicate an increase and a decrease in the gene expression levels, respectively, as indicated in the scale bar. The affiliation of all listed genes with one of the ten signaling pathways listed in Table 1 is presented in the Supplementary Table.