**5. Metamorphic thyroid autoimmunity**

Here we overview the phenomenon of metamorphic thyroid autoimmunity anticipating, that more investigational studies are needed to reveal the underlying mechanism, and larger epidemiological studies are needed to confirm that this finding is not unusual but is rather under-recognized in pediatric population. The term metamorphic thyroid autoimmunity was introduced by Ludgate M. and Emerson H. commenting cases with a conversion from Hashimoto thyroiditis (HT) to GD or vice versa [20–22]. A few years later Wasniewska M et al. aimed to ascertain HT in the history of GD children order to assess the relative frequency of this phenomenon [23]. Based on retrospective data of a cohort of 109 GB children and adolescents without coexistent chromosome abnormalities they calculated the frequency between 3 and 4%. Reporting results they confirmed the existence of a possible continuum between HT and GD within the spectrum of autoimmune thyroid diseases. In search of switching process from HT to GB in patient with either Turner syndrome (TS) or Down syndrome (DS) the same team found that antecedents of HT were significantly more common in chromosomopathy group (9/35 = 25.7%) compared to age-matched GD patients (4/109 = 3.7%) [24]. Guessing the clue of this immunological paradigm it should take into high consideration that attribute of HE is a cell-mediated destruction of thyroid tissue with hypo- or euthyroidism while GB is a TRAB-mediated gland activation presented in hyperthyroidism. In general, thyroid autoimmunity involves loss of tolerance to thyroid proteins in genetically susceptible individuals in association with environmental factors, no single mechanism explains the altered immune-reaction. Further immunological and genetic investigations can add explanatory information to this unusual pendulum swinging thyroid autoimmunity.

## **6. Peculiarities in Down syndrome**

#### **6.1 Asymptomatic vs. cumulative presentation**

Thyroid derangement is the most frequently encountered endocrinopathy in Down syndrome (DS) affecting almost half of the patients (7 - 66%). Based on this fact the life-long monitoring of the thyroid function is recommended for all DS patients. Thyroid abnormalities encompass mainly any kind of hypothyroidism (congenital, primary, subclinical, or overt hypothyroidism), isolated hyperthyrotropinemia, Hashimoto thyroiditis or very rarely GD. Autoimmune thyroid disease is uncommon in young children with Down's syndrome but is common after 8 years of age [25]. A Spanish group [26] reported on three DS children with GD: Two of them were asymptomatic for thyroid hyperfunction (a 14-year-old girl and an 8-year-old boy), while the third child (a 12-year-old girl) presented goiter, nervousness, weight loss and tachycardia. In addition to the typical features of hyperthyroidism, the patient showed right-side heart failure and elevated transaminases, which disappeared with antithyroid treatment. Though annual biochemical screening for early detection of thyroid hypofunction is reasonable, regular auxological and clinical assessment in syndromic patients is also important.

#### **6.2 Metamorphic thyroid autoimmunity**

HT and GB are two different disease entities in the spectrum of thyroid autoimmunity presenting dominantly with hypothyroidism (HT) or with hyperthyroidism (GB). A metamorphosis of both clinical and biochemical phenotype from HT to GD or vice versa has been discussed for more than 10 years [22] based on sporadic cases. A tapered Italian team conducted several retrospective studies to shed light on this phenomenon in pediatric population. In 2015 they published a research paper reconstructing the conversion process from HT to GD and the subsequent evolution of GD in a series of 12 children (7 girls/5 boys) with DS [27]. All patients fulfilled the criteria for diagnosis of HT and GD taking laboratory measurements and ultrasonography scan. Time interval between HT diagnosis and GB presentation ranged from 0.7 to 6.5 years, and Graves' Disease showed a milder clinical and biochemical course in this cohort. Summing up they conclude that "1, DS children might be incline to manifest over time a phenotypic metamorphosis from HT to GH and to subsequently fluctuate from hyperthyroidism to hypothyroidism; 2) in DS GD may have a mild biochemical and clinical course" [27].

#### **6.3 Unusual scenario**

A DS case with an unusual thyroid constellation were published by Nebesio TD and Eugster EA. " A 10-year-old girl with Down syndrome was diagnosed with congenital hypothyroidism in the newborn period due to left thyroid hemiagenesis. Unexpectedly, her hypothyroidism resolved at the age of 3 years. After being off thyroid hormone replacement for 7 years and having normal thyroid function, she developed Graves' Disease with typical signs and symptoms of hyperthyroidism including diarrhea, inattention, and hyperactivity" [28]. This case highlights also the unpredictable course of thyroid disease which may occur in children with Down syndrome.
