Table 1.
(a) Prevalence of autoimmune thyroid disorders and (b) associated non-autoimmune thyroid disorders in pediatric patients with TS, DS, KS, 22q11.2DS, WS, PWS, NS, and NF1 (c) possible underlying mechanisms involved in the pathogenesis of autoimmunity and (d) extrathyroidal autoimmune disorders associated with these syndromes.
| TS | DS | KS | 22q11.2DS | |
|---|---|---|---|---|
| a) ATD (prevalence) | HT (10–42%)* GD (1.7–3%) |
HT (13–46%) GD (6.5‰) |
HT (5.4–10%) GD (rare) |
HT: (5% children, 30% age>17 years) GD (1.8%) |
| b) Non-autoimmune thyroid disorder | Primary hypothyroidism | CH - Incidence: 1:113–1:141 DS live births - mainly due to thyroid hypoplasia Primary hypothyroidism |
Central hypothyroidism Peripheral hypothyroidism |
Thyroid gland anomalies/hypoplasia (~50%) Primary hypothyroidism |
| c) Possible underlying mechanisms implicated in the pathogenesis of autoimmunity | - X-chromosome genes haploinsufficiency - parental X chromosome origin - excessive production of pro-inflammatory cytokines - decreased levels of anti-inflammatory cytokines hypogonadism |
- thymic atrophy and diminished expansion of T and B lymphocytes - altered thymic expression of AIRE - association with MHC class II DQA 0301 allele - altered regulation of pro- and anti-inflammatory cytokines - hyperresponsiveness to IFN |
- immunomodulatory role of sex hormones in the immune response - X-linked gene dosage |
- absent/hypoplastic thymus, ↓AIRE expression - T-cell lymphopenia, ↓ Tregs - restricted T cell repertoires, abnormal T cell activation, B cell dysregulation, Th1/Th2 imbalance - association with HLA-DR14 |
| d) Associated extrathyroidal autoimmune disorders | - CD: ↑risk 4- to 8-fold - T1D, IBD, alopecia areata, vitiligo, psoriasis, lichen sclerosus, JIA, ITP - ↑ risk 4-fold for AD with a male predominance (T1D, Dupuytren's contracture, amyotrophic lateral sclerosis, ankylosing spondylitis and reactive arthritis) |
- In particular: alopecia and vitiligo - CD: ↑ risk >6 years of age - T1D, idiopathic arthritis - Addison disease, chronic autoimmune hepatitis, primary sclerosing cholangitis** |
- SLE: ↑risk 14-fold - T1D - Addison's disease, multiple sclerosis, RA, Sjogren's syndrome - JIA, psoriatic arthritis, polymyositis/dermatomyositis, systemic sclerosis, mixed connective tissue disease, antiphospholipid syndrome, ankylosing spondylitis, primary biliary cirrhosis |
- JIA, ITP (next most common causes after ATD) - autoimmune hemolytic anemia, autommune neutropenia, psoriasis, vitiligo, CD, pernicious anemia/atrophic gastritis, IBD, urticaria, Raynaud phenomenon, rheumatic fever with chorea, T1D |
| WS | PWS | NS | NF1 | |
| a) ATD (prevalence) | Rare | Rare | HT (14.3–60%) | HT: 2.5% GD: rare |
| b) Non-autoimmune thyroid disorder | Thyroid hypoplasia (75%) - Other structural abnormalities: agenesis, hemiagenesis and ectopy Primary hypothyroidism CH (rare) Hyperthyroidism (rare) Central hypothyroidism (rare) |
Mainly central hypothyroidism (6.8%) Primary hypothyroidism CH Ectopic thyroid gland |
Primary hypothyroidism | Central hypothyroidism Primary hypothyroidism |
| c) Possible underlying mechanisms implicated in the pathogenesis of autoimmunity | - both under- and overactivities of disparate Ras effectors - both increased and decreased Ras activities may be implicated in lupus-like autoimmunity - linkage of a susceptibility gene for SLE to 12q24, a locus encompassing PTPN11, encoding SHP-2 SHP-2 inhibits NK cells activation, cytolytic activity and IFN-γ |
- loss of neurofibromin resulting in decreased Fas antigen expression which may prevent apoptosis of CD4+ T cells - lymphoproliferative defects, including thymic and splenic hyperplasia, increased numbers of immature and mature T cells in vivo, but reduced proliferation in response to TCR and |
||
| secretion by NK cells, may mediate inactivation of immunoregulatory receptors and functions as a regulator of NF-κB activation. Increased SHP-2 activity is involved in SLE pathogenesis, modulating T cell proliferation and downstream cytokine production | IL-2R stimulation in vitro, defective proliferative responses in B lymphocytes and thymocytes were shown in NF1-deficient mice | |||
| d) Associated extrathyroidal autoimmune disorders | - CD*** | - Autoantibodies against pituitary | - Vasculitis, vitiligo, anterior uveitis, SLE, CD, antiphospholipid syndrome, and autoimmune hepatitis | - Multiple sclerosis, SLE, membranous glomerulonephritis, IgA nephropathy, mixed connective tissue disease, myasthenia gravis, ankylosing spondylitis, JIA, CD, autoimmune hemolytic anemia, bullous pemphigoid, vitiligo, alopecia areata, T1D |
TS, Turner syndrome; DS, Down syndrome; KS, Klinefelter syndrome; 22q11.2DS, chromosome 22q11.2 deletion syndrome; WS, Williams syndrome; PWS, Prader-Willi syndrome; NS, Noonan syndrome; NF1, Neurofibromatosis type 1; ATD, autoimmune thyroid disease; HT, Hashimoto's thyroiditis; GD, Graves'disease; CH, congenital hypothyroidism; AIRE, autoimmune regulator; MHC, major histocompatibility complex; IFN, interferon; ↓, decreased; Tregs, regulatory T cells; Th, T helper (cell); HLA, human leukocyte antigen; PTPN11, tyrosine-protein phosphatase non-receptor type 11; SHP-2, Src homology phosphotyrosyl phosphatase 2; NK, natural killer (cells); NF-κB, nuclear factor kappa B; CD4, cluster of differentiation 4; IL-2R, interleukin-2 receptor; TCR, T cell receptor; CD, celiac disease; ↑, increased; T1D, type 1 diabetes mellitus; IBD, inflammatory bowel disease; JIA, juvenile idiopathic arthritis; RA, rheumatoid arthritis; ITP, idiopathic thrombocytopenic purpura; AD, autoimmune disease; SLE, systemic lupus erythematosus.
Giménez-Barcons et al. (30).