Down Syndrome and Thyroid Disorders: A Review

Prasher, V. P.

doi:10.3104/reviews.95

Cited by 85 publications

(55 citation statements)

References 114 publications

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“…One of the hypothyroid patients also had celiac disease. Overall, this was a .50-fold increase compared with the prevalence of hypothyroidism in the general population and was in line with the previously reported higher prevalence of hypothyroidism and earlier age at onset observed for this genetic condition (9,24). On the whole, this was consistent with hypothyroidism being the commonest form of thyroid disorder associated with DS (24).…”

Section: Resultssupporting

confidence: 79%

Autoimmune Predisposition in Down Syndrome May Result from a Partial Central Tolerance Failure due to Insufficient Intrathymic Expression of AIRE and Peripheral Antigens

Giménez‐Barcons

Casteràs

Armengol

et al. 2014

The Journal of Immunology

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Down syndrome (DS), or trisomy of chromosome 21, is the most common genetic disorder associated with autoimmune diseases. Autoimmune regulator protein (AIRE), a transcription factor located on chromosome 21, plays a crucial role in autoimmunity by regulating promiscuous gene expression (pGE). To investigate if autoimmunity in DS is promoted by the reduction of pGE owing to dysregulation of AIRE, we assessed the expression of AIRE and of several peripheral tissue-restricted Ag genes by quantitative PCR in thymus samples from 19 DS subjects and 21 euploid controls. Strikingly, despite the 21 trisomy, AIRE expression was significantly reduced by 2-fold in DS thymuses compared with controls, which was also confirmed by fluorescent microscopy. Allele-specific quantification of intrathymic AIRE showed that despite its lower expression, the three copies are expressed. More importantly, decreased expression of AIRE was accompanied by a reduction of pGE because expression of tissue-restricted Ags, CHRNA1, GAD1, PLP1, KLK3, SAG, TG, and TSHR, was reduced. Of interest, thyroid dysfunction (10 cases of hypothyroidism and 1 of Graves disease) developed in 11 of 19 (57.9%) of the DS individuals and in none of the 21 controls. The thymuses of these DS individuals contained significantly lower levels of AIRE and thyroglobulin, to which tolerance is typically lost in autoimmune thyroiditis leading to hypothyroidism. Our findings provide strong evidence for the fundamental role of AIRE and pGE, namely, central tolerance, in the predisposition to autoimmunity of DS individuals.

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Section: Resultssupporting

confidence: 79%

Autoimmune Predisposition in Down Syndrome May Result from a Partial Central Tolerance Failure due to Insufficient Intrathymic Expression of AIRE and Peripheral Antigens

Giménez‐Barcons

Casteràs

Armengol

et al. 2014

The Journal of Immunology

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“…The prevalence of autoimmune thyroid disease has been reported to be at least fourfold higher in children with DS than in the general population (25)(26)(27), but a recent longitudinal study suggests that that this may be an overestimation (28). Celiac disease may be 10 times more common in DS populations (2,29).…”

Section: Islet Autoantibodiesmentioning

confidence: 88%

Early-Onset, Coexisting Autoimmunity and Decreased HLA-Mediated Susceptibility Are the Characteristics of Diabetes in Down Syndrome

et al. 2013

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OBJECTIVEdDown syndrome (DS) is associated with an increased risk of diabetes, particularly in young children. HLA-mediated risk is however decreased in children with DS and diabetes (DSD). We hypothesized that early-onset diabetes in children with DS is etiologically different from autoimmune diabetes.RESEARCH DESIGN AND METHODSdClinical and immunogenetic markers of autoimmune diabetes were studied in 136 individuals with DSD and compared with 194 age-and sex-matched individuals with type 1 diabetes, 222 with DS, and 671 healthy controls. HLA class II was analyzed by sequence-specific primed PCR. Islet autoantibodies were measured by radioimmunoassay.RESULTSdAge at onset of diabetes was biphasic, with 22% of DS children diagnosed before 2 years of age, compared with only 4% in this age-group with type 1 diabetes in the general population (P , 0.0001). The frequency of the highest-risk type 1 diabetes-associated HLA genotype, DR3-DQ2/DR4-DQ8, was decreased in both early-and later-onset DSD compared with age-matched children with type 1 diabetes (P , 0.0001), although HLA DR3-DQ2 genotypes were increased (P = 0.004). Antibodies to GAD were observed in all five samples tested from children diagnosed at #2 years of age, and persistent islet autoantibodies were detected in 72% of DSD cases. Thyroid and celiac disease were diagnosed in 74 and 14%, respectively, of the DSD cohort.CONCLUSIONSdEarly-onset diabetes in children with DS is unlikely to be etiologically different from autoimmune diabetes occurring in older DS children. Overall, these studies demonstrate more extreme autoimmunity in DSD typified by early-onset diabetes with multiple autoimmunity, persistent islet autoantibodies, and decreased HLA-mediated susceptibility.

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“…The early diagnosis of thyroid dysfunctions is important and pediatricians can often recognize them in their early stages, by maintaining an appropriate index of suspicion. Recognition of HT can be very difficult because it has a subtle presentation and symptoms overlap with features of DS, including impaired intellectual development in young children, decreased linear growth, dry skin and fine hair, excess weight, dentition abnormalities, and decreased physical activity [2]. In our DS children with thyroid dysfunctions the incidence of replacement therapy was 41% over the 10-year period.…”

Section: Discussionmentioning

confidence: 99%

“…Down's syndrome (DS), the most common chromosomal disorder, is associated with several concomitant diseases, including thyroid dysfunction [1,2,3]. Thyroid disorders are more common in patients with DS than in the general population and they have been estimated to range between 4 and 19.5% [4,5,6,7,8] with an increase in frequency, up to 54%, as the children age [5,9,10].…”

Section: Introductionmentioning

confidence: 99%

Ten-Year Longitudinal Study of Thyroid Function in Children with Down's Syndrome

et al. 2014

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Background/Aims: The natural history of thyroid function in children with Down's syndrome is relatively unknown. We hypothesized that in these patients the occurrence of thyroid dysfunction rises during development. Methods: Thyroid function was assessed yearly in 145 children with Down's syndrome, all followed from birth up to 10 years of age. Heteroskedastic binary and ordinary logistic regression for repeated measures was used to evaluate the relationship of thyroid function with continuous time. Results: Congenital hypothyroidism was detected in 7% of cases. The probability of acquired thyroid dysfunction increased from 30% at birth to 49% at 10 years (p < 0.001). The subclinical hypothyroidism was nearly stable during the follow-up. The probability of hypothyroidism increased from 7 to 24% at 10 years (p < 0.001). Positive anti-thyroglobulin antibodies were associated with higher odds of more severe hypothyroidism (odds ratio 3.6). Positive anti-thyroid peroxidase antibodies were a better predictor of more severe hypothyroidism (odds ratio 6.1). Diffuse hypoechogenicity on thyroid ultrasound was found in 34 out of 145 children. Conclusion: The probability of thyroid dysfunction increasing during development is higher than previously reported. Such children should be carefully monitored annually to early identify thyroid dysfunction.

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Down Syndrome and Thyroid Disorders: A Review

Cited by 85 publications

References 114 publications

Autoimmune Predisposition in Down Syndrome May Result from a Partial Central Tolerance Failure due to Insufficient Intrathymic Expression of AIRE and Peripheral Antigens

Autoimmune Predisposition in Down Syndrome May Result from a Partial Central Tolerance Failure due to Insufficient Intrathymic Expression of AIRE and Peripheral Antigens

Early-Onset, Coexisting Autoimmunity and Decreased HLA-Mediated Susceptibility Are the Characteristics of Diabetes in Down Syndrome

Ten-Year Longitudinal Study of Thyroid Function in Children with Down's Syndrome

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