Studying a large cohort of children with Graves' disease and Hashimoto's thyroiditis, we find that 4.6% and 2.0% of children, respectively, have vitiligo. Interestingly, the children with vitiligo and Graves' disease were much younger than those with Hashimoto's disease and vitiligo.
Graves' disease is rare in the pediatric population, with a prevalence of about 1 per 10,000 individuals [12, 13]. In children, the peak age of Graves' disease is 11-15 years, and it is three to five times more common in females than in males. In young children, no gender differences have been found [14, 15].
When Hashimoto's thyroiditis occurs in pediatric patients, it is most common in adolescence, and is rare before the age of 3 . The incidence of Hashimoto's in adolescence ranges from 1-2% of individuals [18–20]. However, an NHANES study found that 6.3% of adolescents from 12 to 19 years of age had positive anti-thyroglobulin antibodies and 4.8% had anti-thyroid peroxidase antibodies . Another study of 160 children with antibodies consistent with euthyroid autoimmune thyroiditis had a mean age of 9.1 years .
As T-cell-mediated autoimmune diseases, Graves' disease and Hashimoto's thyroiditis have lymphocytic infiltration into thyroid parenchyma [10, 14, 19]. In Graves' disease, the antibodies bind to thyrotropin receptors, stimulating thyroid hormone production [10, 14, 19]. In Hashimoto's thyroiditis, lymphocytic infiltration leads to thyroid destruction . Similarly, skin biopsies from vitiligo patients show dermal and epidermal lymphocytic infiltrate, consisting of activated T cells, which are thought to cause melanocyte destruction .
Vitiligo is the most common acquired pigmentary disorder in children and adults, with an incidence of approximately 1% in the general population [1–5]. Vitiligo results from loss of melanocytes, which leads to well-demarcated depigmentation in macules or patches on skin, overlying hair, and/or mucus membranes. Onset of vitiligo prior to age 20 years occurs in approximately 50% of cases and before 10 years in approximately 25%, with a nearly equal gender ratio [1, 4–7]. Several etiologies for vitiligo have been proposed, and significant evidence supports an autoimmune pathogenesis, with circulating autoantibodies that target melanocyte antigens and subsequently attack and destroy melanocytes [1, 3–5]. This theory is supported by the recent identification of genes linked to vitiligo that are involved in innate immunity [5, 6].
Studies have shown an association between vitiligo and thyroid disease with an 8-25% incidence of autoimmune thyroid disease in patients with vitiligo [2, 3, 5, 6]. Hashimoto's thyroiditis is seen in the majority of adult patients with vitiligo and autoimmune thyroid disease [2, 3, 22]. As in our cohort, vitiligo was diagnosed before thyroid disease in most patients in these studies [1, 3].
The age of onset of vitiligo has been found to be earlier in families with a history of multiple autoimmune diseases . This may be at least in part due to variants of genes including NALP1 that have been associated with susceptibility to vitiligo and autoimmune thyroid disease . This gene regulates the immune system, including activating the inflammatory cascade, and is expressed on T cells and Langerhans' cells .
Studies have also identified immunogenetic associations with vitiligo and autoimmune thyroid diseases. Vitiligo is associated with HLA-DR4, and thyroid disease is associated with Class 1 and Class II HLA including HLA-DR [8–10]. Graves' disease has been associated with HLA-DR3 [9, 14, 20]. In comparison, Hashimoto's thyroiditis has not had a consistent HLA-association, but HLA-DR has been associated . Other studies have shown an increase in CD4+ T-lymphocytes in addition to an elevated CD4+/CD8+ ratio in vitiligo patients , a finding that is present in patients with autoimmune thyroid disease [9, 10].
Similarly, patients with vitiligo and at least one other autoimmune condition, including either Graves' disease or Hashimoto's thyroiditis, have been found to have a cytotoxic T lymphocyte antigen-4 (CTLA-4) polymorphism, which is involved in T cell apoptosis [8–10]. In Graves' disease, a specific CTLA-4 polymorphism has been associated with an early age of onset and severity of presentation . Thus in the future, it will be interesting to characterize the genetic associations of vitiligo and other autoimmune diseases in the pediatric population.
Overall, our observations of a significant incidence of vitiligo in children with thyroid disease shows that children with thyroid disease should be screened for vitiligo, especially young children with Graves' disease. Thyroid screening is already recommended annually for patients with vitiligo [1–6]. The occurrence of Graves' disease and vitiligo in young children further supports the notion that the nature of the autoimmune disorder in the young population differs from that seen in older children.