More Medical Issues in Down's Syndrome. A conference held under the auspices of the Royal Society of Medicine DIABETES Forum on Learning Disability and The Down's Syndrome Medical Interest Group. Royal Society of Medicine, London, Thursday 26th April 2001 AND AUTOIMMUNE Chaired by Dr Patricia Jackson, Edinburgh and Dr Liz Marder, Nottingham Type 1 diabetes and other autoimmune disorders in Down's syndrome Summary of a presentation by Dr Julian Shield Consultant Senior Lecturer, Department of Child Health, University of Bristol Autoimmunity is very prevalent in people with Down's years (p > 0.0001) and 15% before one year of age (Figure 1, syndrome, but it is a much under-researched area. Type 1 dia- Shield et al, 1999). This is in line with clinical experience and betes is one of the manifestations of autoimmune disregula- reports from other studies. tion which is over represented. Other disorders which occur in Clinical presentation in those with Down's syndrome is no excess are listed in Panel 1. different than in the general population other than it may be more acute and is often at a younger age. This is important as this young age group can be very difficult to treat. Younger Panel 1: Autoimmune manifestations in Down's children can have very arbitrary eating and feeding patterns. syndrome Doctors like to give insulin at certain times and may find it · Type 1 diabetes · Alopecia areata difficult to adapt schedules to a young child's variable eating · Thyroid disease · Chronic active hepatitis habits. · Vitiligo · Coeliac disease Putative reasons for earlier onset of In the general population, approximately 2 out of 1000 type 1 diabetes (0.2%) children will develop type 1 diabetes in childhood. · There may be a more aggressive autoimmune condition. It is generally acknowledged that for people with Down's When considering the range of autoimmune conditions syndrome, there is around a 10 times increased prevalence. which occur, sometimes concurrently, in people with Estimates vary and range from 0.33 to 10.6%. Down's syndrome, it is possible to argue that around one- Not only is the prevalence of type 1 diabetes increased in third may have a very aggressive autoimmune phenotype. those with Down's syndrome, but the condition also develops In the general population, whether diabetes develops at 2 at a younger age. In the general population very few children or 15 years of age, auto-antibodies will have been present develop type 1 diabetes (IDDM) under one year of age. By from an early age, possibly from birth. If the autoimmune contrast, in a recent study of 59 children with Down's syn- process is not very aggressive there will only be a gradual drome and IDDM, 22% developed type 1 diabetes before two reduction of islet cell mass so the condition may not pre- sent clinically until around age 15 years. If however, as may be the case in Down's syndrome, there is a particu- larly aggressive autoimmune phenotype, islet cells will be destroyed more rapidly and the condition will present earlier. · The islet cell population may be more prone to cell- mediated destruction. It is possible that in children with Down's syndrome, the islet cells are weaker and more liable to be destroyed, or they may be reduced in number and therefore any culling of islet cells by autoimmune destruction will result in an earlier manifestation. Other autoimmune disorders Thyroid disease Thyroid disease is commonly screened for in people with Down's syndrome. As with type 1 diabetes, the condition is Figure 1: Variations in age of diagnosis of type 1 dia- more prevalent and age at onset is earlier than in the general betes in children, illustrating the earlier onset in children population. Approximately 30% of those with Down's syn- with Down's syndrome (Arch Dis Child 1999;81:147­50, drome will develop thyroid disorder, most commonly hypothy- with permission from the BMJ Publishing Group). roidism, before age 25 years. Autoimmunity often underlies the © Down's Syndrome Medical Interest Group · Children's Centre · City Hospital Campus · Nottingham NG5 1PB · www.dsmig.org.uk T: 0115 962 7658 ext 45667 · F: 0115 962 7915 · info@dsmig.org.uk DSMIG is indebted to the Down's Syndrome Association who have met all the production costs for this summary. problem and about 40% of children with Down's syndrome tain conditions. This possibility was investigated by looking have thyroid antibodies before age 20, thus more manifest at the AIRE gene on chromosome 21 which causes autoim- surrogate markers of autoimmunity than have overt disease. mune polyglandular syndrome type 1 ­ a condition which This appears to be a recurrent theme in Down's syndrome. shares many features with Down's syndrome. However no increase in disomic homozygosity was found. Coeliac disease Another cause could be overexpression of one of the The prevalence of coeliac disease in Down's syndrome is also genes on chromosome 21 ­ if there are three identical genes much higher than in the general population and is particularly they may all be active and therefore strongly expressed. This prevalent, though often sub-clinical, among those with dia- is true of superoxide dismutase (SOD) which exhibits 150% betes. When treated with a gluten-free diet many of these normal activity in people with Down's syndrome as all three children suddenly feel a lot better, and the risk of small bowel copies of the regulatory gene are active. If there is an auto- lymphoma later in life is reduced. Strong consideration immune gene which is over expressed in this way in people should therefore be given to routine coeliac screening for with Down's syndrome, this may increase their likelihood of those with Down's syndrome who have diabetes. developing diabetes or other autoimmune conditions. Why is autoimmune disease more prevalent Potential autoimmune genes on chromosome 21 among people with Down's syndrome? Chromosome 21 has between 500 and 800 genes. Possibly There is abundant evidence of immune dysregulation in peo- less than 20 are responsible for the major phenotypic features ple with Down's syndrome which may make this group more of the syndrome. These lie in a critical region on the distal predisposed to autoimmune disease. Known factors suggest- segment of the long arm (22.3q). However, the genes for other ing immune dysregulation in Down's syndrome include: frequently associated conditions are located outside this criti- · Abnormal thymus development /morphology cal region which may explain the phenotypic variation among · Altered lymphocyte sub-populations in peripheral those with the syndrome. Panel 2 lists genes which map to blood and thymus with evidence of 'T' cell activation chromosome 21 but outside the critical region whose overex- and premature ageing effects pression may cause autoimmune disorder. · Increased susceptibility to infections · Increased risk of malignancy. Panel 2: Potential autoimmune genes How is the genetic susceptibility to autoim- AIRE ­ causes autoimmune polyglandular syn- mune disease conferred? drome type 1. Amyloid precursor protein (APP) ­ overexpression There are two ways in which genetic susceptibility to autoim- may lead to tissue destruction, increased tissue mune disease is conferred in Down's syndrome: inflammation and organ damage. · The HLA alleles which confer genetic susceptibility Superoxide dismutase (SOD) ­ increased SOD to autoimmunity may be more prevalent in the Down's activity in Down's syndrome, saturation of the sys- syndrome population. tem by excessive amounts of hydrogen peroxide · The three copies of chromosome 21 may cause disordered causes hydroxyl ions to be formed (Fenton's reac- function of some genes which may be responsible for tion), resulting in organ damage. autoimmunity in general. Ligand of ICOS (LICOS) ­ overexpression leads to increased lymphocyte damage and cytokine produc- HLA genotypes tion, thereby increasing the severity of organ damage. The prevalence of different HLA types in children with Down's syndrome was investigated in a pilot study. The HLA region which controls the immune system is found on chro- Summary mosome 6. Those in the general population who develop dia- · Autoimmunity is very prevalent in people with Down's betes are usually DR3/4 (one DR3 and one DR4 from their syndrome. However, this is a much under researched area. parents). The study showed that only about 30% of children · Type 1 diabetes, thyroid disease and coeliac disease are with Down's syndrome and diabetes possess DR3/4 in con- just some of the autoimmune conditions which are over trast to a general population figure between 60 and 70%. This represented in those with Down's syndrome. suggests that there is a different genetic factor in people with · Genetic susceptibility to autoimmune disease in Down's Down's syndrome that predicts whether or not they are going syndrome may be conferred by the prevalence of certain to develop diabetes. An interesting finding was an excess of HLA types and/or gene dose effects relating to the extra DR4 in the children with Down's syndrome who did not have copy of chromosome 21. diabetes. If this is confirmed in a larger study it could be related not only to diabetes, but also to the higher prevalence Further reading of thyroid and coeliac disease. Anwar AJ, et al. Diabetic Medicine 1998:15:160­3. Book L, et al. Am J Med Genet 2001:98:70­744. Gene dose effects Ivarrson S A, et al. Acta Paediatr 1997:86:1065­1067. There are several mechanisms by which the presence of an extra chromosome 21 could influence autoimmunity. One of Shield JP, et al. Arch Dis Child 1999;81:147­50. these is the possibility of disomic homozygosity. If two iden- tical chromosomes are inherited from the parent of origin of A complete transcript of this presentation, together the trisomy this may increase the propensity to develop cer- with references, is available at www.dsmig.org.uk. © 2002 Down's Syndrome Medical Interest Group. Produced by Oxford PharmaGenesisTM Ltd, UK