We report male monozygotic twins who presented with neonatal diabetes mellitus (NDM) within an autoimmune context. They were born to unrelated healthy parents after 36 weeks of uncomplicated pregnancy. Family history was unremarkable. The clinical history of the patients was almost identical; both twins were admitted on the 12th and 25th days of life, respectively, because of poor feeding, dehydration, lethargy, metabolic acidosis, severe watery diarrhea, and persistent hyperglycemia (>17 mmol/1). It was very difficult to stabilize diabetes on the conventional subcutaneous insulin schedule, so intravenous treatment was started in both patients. High levels of thyroid-stimulating hormone were found by routine screening tests, and increased serum levels of anti-thyroglobulin and anti-thyroid peroxidase antibodies were detected. Moreover, islet cell antibody and GAD-reactive autoantibodies were found, whereas insulin autoantibodies, serum enterocyte autoantibodies, antiparietal cells, and anti-endomisium were normal. No serum levels of these autoantibodies were detected in the mother. Extensive testing(lymphocyte subpopulation, CD4-to-CD8 ratio, and mitogenic response) failed to reveal immunological defects. Serologic tests for viral infections were negative. IgE concentration was normal. HLA typing did not show type 1 diabetes-related haplotypes.

The subsequent clinical course was characterized by persistent watery diarrhea (volumes ≤ 100 ml/kg per day) unresponsive to total parenteral nutrition, a failure to thrive, recurrent infections, and brittle diabetes(values from 5 to 25 mmol/l).

Clinical conditions progressively worsened, and both patients died of sepsis within the third month of life. Postmortem examination showed a marked infiltration of mononuclear cells of the pancreas, intestine, lung, and thyroid.

The infants we have described share several features with an extremely rare X-linked syndrome of intractable diarrhea, polyendocrinopathy, and fatal infection(1,2). Certainly, the most striking outcome of this report is that NDM is associated with immune dysregulation.

It is believed that NDM is not related to an autoimmune phenomenon because autoantibodies have never been reported and because the autoimmune destructive process is a very slow one, and it may last years; therefore, this process would unlikely begin or develop in utero and become clinically evident at birth.

Nevertheless, at least three types of evidence support the autoimmune nature of diabetes in our patients: 1) the presence ofβ-cell-reactive autoantibodies, 2) the association with other typical autoimmune diseases (namely thyroiditis and enteropathy), and 3) the identification of insulitis with a massive infiltration of mononuclear cells at necropsy.

Undoubtedly, the histological and immunological findings are typical of the autoimmune-type diabetes. A striking finding is that insulitis can be clinically evident very shortly after birth. Nevertheless, it would be very interesting to speculate how these findings relate to the absence of specific HLA antigens of susceptibility. The anti-islet response could be part of a more global immune hyperreactivity caused by the loss of the immune-regulatory function, without apparent requirement for an autoantigenic driving force. Our experience further suggests that NDM includes more than one disorder, so more than one mechanism might be implicated in the etiology. Although it is difficult to formulate a global hypothesis explaining our findings, evidence supports the possibility that autoimmunity might, in someway, be involved in at least selected cases of NDM.

Powell BR, Buist NR, Stenzel P: An X-linked syndrome of diarrhea,polyendocrinopathy, and fatal infection in infancy.
J Pediatr
Peake JE, McCrossin RB, Byrne G, Sheperd R: X-linked immune dysregulation, neonatal insulin-dependent diabetes, and intractable diarrhea.
Arch Dis Child