ISSN 1662-4009 (Online)

ESPE Yearbook of Paediatric Endocrinology (2019) 16 2.6 | DOI: 10.1530/ey.16.2.6

Trisomy 21 is a cause of permanent neonatal diabetes that is autoimmune but not HLA associated

Johnson MB, De Franco E, Atma W, Greeley S, Letourneau LR, Gillespie K, International DS-PNDM consortium, Wakeling MN, Ellard S, Flanagan SE, Patel KA & Hattersley AT



To read the full abstract: Diabetes. 2019 Apr 8. pii: db190045. doi: 10.2337/db19-0045.

This study assessed the incidence of permanent neonatal diabetes mellitus (PNDM) in patients with Trisomy 21.

Patients with Trisomy 21 have an increased prevalence of autoimmune conditions, such as Type 1 diabetes, celiac disease, alopecia, vitiligo and autoimmune thyroid disorders (Hashimoto’s thyroiditis and Graves’ disease). Childhood onset autoimmune diabetes is 4-times more common in patients with Trisomy 21 than the general population. Diabetes in patients with Trisomy 21 is usually autoimmune and associated with the presence of autoantibodies and Human Leucocyte Antigen (HLA) haplotypes which increase the risk of diabetes. It is not known if Trisomy 21 can present with permanent neonatal diabetes mellitus (PNDM).

In this study, the authors looked at a large cohort of patients with PNDM. 13 patients with Trisomy 21 were identified as having developed PNDM in the first 6 months of life and in about 44% of these patients, one or more autoantibodies were positive. However interestingly none of these patients had the HLA haplotype associated (HLA DR3/DR4) with the increase risk of developing diabetes, suggesting that the PNDM in Trisomy 21 is not HLA associated. These data imply that there is prenatal onset of beta cell dysfunction in patients with Trisomy 21 and PNDM. Previous post mortem studies on pancreatic tissue from non-diabetic infants with Trisomy 21 have shown that there is no deficiency of pancreatic beta-cells (Butler AE et al.). Trisomy 21 is a cause of PNDM, and the underlying mechanism of the diabetes is likely to involve autoimmunity against the beta cells. A complex interaction between multiple genes (AIRE, UBASH3A, IFNAR1, IFNAR2, IFNGR2 and IL1ORB) on chromosome 21 may be responsible for the increased autoimmunity in patients with Trisomy 21.

Diabetes in patients with Trisomy 21 seems to be a heterogenous condition and consists of a subgroup diagnosed very young (including PNDM) which is autoimmune but not HLA mediated and a second group, usually presenting beyond infancy, that is similar to Type 1 diabetes in the non-Trisomy population and has a strong HLA association.

Reference: Butler AE, Sacks W, Rizza RA, Butler PC. Down Syndrome-Associated Diabetes Is Not Due To a Congenital Deficiency in β-Cells. J Endocr Soc. 2017 Jan 1;1(1):39–45.