Down's syndrome

This, the most common genetic cause of birth disorders, is due to trisomy (an additional copy) of chromosome 21, resulting in a wide range of developmental disorders. The extent of physical or mental disability may vary widely from one individual to the next. The characteristic appearance includes short stature, a small rounded head flattened posteriorly, broadening of the neck, slanting eyes, a flattened nose, small broad hands with a single palmar crease and white (Brushfield) spots overlying the iris of the eye. Associated defects include intellectual impairment ranging from moderate to severe, and congenital heart defects (often atrial or ventricular septal defects), which occur in up to 50% of children. Delayed complications include leukaemia and early onset dementia. Autoimmune diseases including thyroid disorders, type 1 diabetes and coeliac disease are more common in Down's syndrome. As compared with sporadic type 1 diabetes, there is an excess of cases presenting before the age of 3. Type 2 diabetes may also present at an early age in Down syndrome due to obesity and insulin resistance.


Down’s syndrome results from an extra copy of chromosome 21
Down’s syndrome results from an extra copy of chromosome 21
Down’s syndrome (trisomy 21) is the most frequent genetic birth defect (1:700 live births), affecting some 300,000 people in the US and 30,000 in the UK[1] [2].

Autoimmunity in Down's syndrome

The prevalence of autoimmune thyroid disease is at least four-fold higher in children with Down's syndrome than in the general population[3][4] and celiac disease may be 10-40 times more common[5][6][7]. Children with Down's are also at a considerably increased risk of diabetes[8][9].

Diabetes in Down's syndrome

In a questionnaire-based study of 20,362 patients the US and UK the observed prevalence of diabetes diagnosed before age 20 in the Down's syndrome population was some six times higher than expected[10].

Other studies have suggested an approximately four-fold increase in childhood diabetes9 [11]. In a Danish study, the prevalence of Down's syndrome in the background population was 0.09%, whereas a prevalence of Down's syndrome in type 1 diabetes patients of 0.38% (95% CI 0.17-0.75) was observed, corresponding to a 4.2-fold increased prevalence compared with the background population[12].

Phenotypic Features

Several studies have observed that onset of diabetes appears to be earlier in children with Down’s syndrome[13][14] and a German group recently reported that diabetes onset during the first 3 years of life occurred in 18.9% of Down's syndrome patients with diabetes compared with 6.4% of children with sporadic type 1 diabetes[15].

Classification of diabetes in these studies was made clinical grounds alone, but most appear to have type 1 diabetes14. A study based on ketonuria and insulin requirement within a month of diagnosis found that this was 10 times more common in Down's than in the rest of the population8.

The first study of the immunogenetic characteristics of diabetes in unaffected children with Down’s syndrome showed that 6% had combinations of two or more islet autoantibodies, predictive of future type 1 diabetes[16].

Role of the HLA system

Analysis of type 1 diabetes HLA genotypes proved more confusing. While there was an increased frequency of type 1 diabetes associated HLA DRB104 and DRB103 genotypes compared to the general population, the frequency was reduced compared to age matched children with type 1 diabetes [16]. This suggests that genes on chromosome 21 are likely to increase the penetrance of diabetes in children with DS.

Why is Autoimmunity Enhanced in Down's syndrome?

Overall, a clinical picture of diabetes in DS children is emerging with earlier onset diabetes and decreased HLA mediated susceptibility – why might this be? Over-expression of type 1 diabetes associated genes on chromosome 21 is one possibility. GWAS identified and replicated a chromosome 21q22.3 type 1 diabetes associated locus[17][18]. The candidate gene is the Ubiquitin associated and SH3 domain containing A (UBASH3A) which is expressed in spleen and peripheral blood lymphocytes[19] and regulates T cell signalling [20]. Over-expression of UBASH3A may therefore provide one candidate for the increased frequency of autoimmune disease in Down’s syndrome.

A second is immune cell dysfunction which is well established in DS. A smaller thymus in DS children has been reported several times[21][22], and total lymphocyte numbers, including CD4 and CD8 T cell subsets are decreased, particularly in the first two years of life. Recent analysis of protein and gene expression in surgically removed thymuses from 14 DS patients compared with 42 age-matched controls showed reduced expression of AIRE, a chromosome 21 gene product that regulates ectopic expression of tissue specific antigens in thymic medullary epithelial cells, a crucial mechanism for thymic T cell selection [23]. This could contribute to the increased risk of multiple autoimmunity and the earlier onset of diabetes that we have observed.

The increased frequency of diabetes in individuals with DS may also reflect a beta cell defect; perhaps resulting from aberrant expression of the free radical scavenger Cu,Zn-superoxide dismutase (SOD-1) on chromosome [21].

Clinical Aspects

There are few clinical reports as to the clinical management and outcome of diabetes in Down's syndrome, but it has been noted that glucose control equivalent to that of non-Down's children can be achieved with simple insulin regimens8. Equally little is known about the impact of late complications of diabetes in this population.

Since obesity is common in Down's syndrome, older patients might be expected to develop a "mixed" form of diabetes combining features of immune-mediated β-cell loss with overweight and insulin resistance. The combination of insulin plus metformin would appear rational in this situation but detailed studies of diabetes in those diagnosed in adulthood are required to prove this hypothesis.


Down's syndrome is important as a cause of type 1 diabetes in its own right, and may also provide insight into the mechanisms of enhanced autoimmunity in other populations. It certainly merits more clinical and research attention than it has to date attracted.

Further information

Diaploidy, an international collection of biological samples from people with Down’s syndrome and Diabetes, is currently under way. Please contact:


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