**7. Coincidence in polyendocrinopathy APS3**

The autoimmune polyglandular syndromes (APS1-4) encompass a wide clinical spectrum of disease with different (monogenic/complex) genetic etiologies and heterogeneous presentation. APS2 is defined by presence of primary adrenocortical insufficiency with either autoimmune thyroid disease or type 1 diabetes mellitus in the same patient. The clinical diagnosis of APS3 requires the presence of an autoimmune thyroid disease and an additional autoimmune illness other than Addison's disease; a frequent combination is pernicious anemia, vitiligo, alopecia, myasthenia gravis and Sjögren sy. Thyroid disease purports a variety of thyroid disorders. Hypothyroidism is more common than Graves' Disease, and GD tends to manifest at a younger age. Recently Klenczar K and coworkers reported on a 11-year-old female patient, who presented coincidence of T1DM with other autoimmune diseases, such as Graves-Basedow's disease, myasthenia gravis, vitiligo, and IgA deficiency [29]. The clinical picture of this case fulfilled the criteria of autoimmune polyglandular syndrome type 3.

## **8. Unexpected coexistence**

Stickler syndrome is a rare genetically heterogeneous disorder of the connective tissue, caused by abnormal synthesis of type II, XI, or IX collagen. It is characterized by a distinctive facial appearance, eye abnormalities, hearing loss and joint problems. Ocular involvements are early onset cataract, myopia, abnormal vitreous humor, retinal detachment, and most of the patients exhibit short stature. Onesimo R et al. reported on a 5-year-old girl affected by Stickler syndrome who

*Unusual Presentation and Rare Comorbidity of Graves-Basedow's Disease in Children DOI: http://dx.doi.org/10.5772/intechopen.97577*

was diagnosed with GD in preclinical state, during health supervision and evaluation by pediatric endocrinologist for short stature [30]. None of her family member suffered from autoimmune thyroid disorder and her medical history was negative for autoimmune disease. Association between Stickler's syndrome and GD in this case seems to be an incidental coexistence.

#### **9. Reconstitution Graves' Disease**

Reviewing the manuscripts on Graves' Disease and rare comorbidity, a new issue has been raised. Growing numbers of publication on the association between biological treatment for life-threatening and/or medication-refractory disorders, and the development of autoimmune hyperthyroidism in adults, call the attention to secondary GD [31, 32]. The use of different modality targeting the immune system as a curative therapy (e.g. hematopoietic stem cell transplantation /HSCT/, antithymocite globulin/ATG/, antiretroviral therapy/ART/etc.), has had a profound impact on clinical outcomes. A subset of patients may experience immune restoration disease (IRD)/immune reconstitution inflammatory syndrome (IRIS) affecting the thyroid gland in two form, such as Hashimoto thyroiditis or Graves' hyperthyroidism. Although both are more common in children because of early thymic damage, it has received little attention in pediatric literature [33]. Sporadic cases were reported on challenging autoimmune processes: Defective T-cell function take place during the pathogenesis both of aplastic anemia (AA) and GD. Antithyroid drugs used for the management of GD may induce AA and GD may occur following treatment of severe aplastic anemia (SAA). The latter occurred in a 11-year-old girl who had been treated with allogenic HSCT at age of 8 years as having severe acquired AA [34]. A case of another child was published earlier with chronic relapsing severe aplastic anemia and GD [35]. Authors supposed a close relation in manifestation of hypertyroidism due to withdrawal of immunosuppressants. In adult patients the secondary GD may exhibit a fluctuating course, with alternating phases of hyperand hypothyroidism, due to the coexistence of TRAb with stimulating and blocking function [36]. Clinicians need to remain vigilant when initiating immune reconstitution therapy, and a careful management and follow-up for thyroid function after these treatments are essential.

#### **10. Discussion**

In this chapter we presented a spectrum of unusual clinical findings, signs of Graves-Basedow's disease in childhood, but atypical laboratory results. Less common and less distinctive features detailed above are well documented in adults, which suggests that these are neither age-dependent nor characteristic to pediatric GD. Though the mechanism remains uncertain in majority of unusual manifestations, the recovery that occurs parallelly with restoration of euthyroidism, gives the evidence of their relation to GB hyperthyroidism. Metamorphic thyroid autoimmunity, a phenomenon of conversion from Hashimoto thyroiditis to Graves' Disease is also summarized without guessing the clue of this immunological paradigm. Existence of a continuum between HT and GD within the spectrum of thyroid autoimmunity is confirmed in pediatric population without coexistent chromosome abnormalities, also in children with Turner or Down syndrome. Beside this peculiar event sequence, GD in DS patient can be insidious by presenting delayed clinical symptoms even with multiple organ derangements. In some rare syndromic disorder regular clinical assessment and biochemical screening supports to reveal

the occurrence of Graves' hyperthyroidism. Finally, a very vulnerable population with malignancy, immune deficiency syndromes, hemoglobinopathies and other disorders attract attention with a possible secondary GB following immune reconstitution therapy. Awareness about the relation of these remote findings to GD, or frequent coexistence with GD is important for early diagnosis, and a reasonable suspicion for Graves' Disease may ultimately help to prevent unnecessary investigations and treatment.
