Spontaneous remission of pendulum swinging thyroid disease in Down syndrome

Background

The prevalence of hyperthyroidism in Down syndrome is estimated to be 0.66% compared to 0.02% in the general population (1). Graves’ disease (GD) in children and adolescents with Down syndrome has a similar prevalence of ophthalmopathy to the reference population; however, important differences do exist (2). Notably, it is more commonly associated with other autoimmune disorders and is more frequently the result of progression from Hashimoto thyroiditis (HT) (3, 4). Furthermore, the age at diagnosis is younger and there is no female preponderance (1, 2). De Luca and colleagues (2) reported lower rates of relapse on antithyroid drugs and higher remission rates post withdrawal with no patients requiring definitive therapies. However, this contrasts with the results of some other studies (1).

GD occurs due to the effects of antibodies binding to and stimulating the TSH receptor (thyrotropin-stimulating antibodies (TSAb)) (5). TSH receptor-blocking antibodies (TBAb) are, on the other hand, an uncommon cause of hypothyroidism. Rare patients who have both TSAb and TBAb can develop fluctuations between hyperthyroidism and hypothyroidism or vice versa in what is variably termed ‘oscillating’ or ‘pendulum swinging’ thyroid dysfunction (6). We describe the clinical course and response to the treatment of a child with Down syndrome with this rare disorder and an unanticipated clinical outcome of prolonged remission.

Case presentation and investigation

A 9-year-old girl with Down syndrome attended her annual health evaluation. Heart rate and blood pressure were normal for age. She had no goitre, no ophthalmopathy and no dermopathy. Her height was 124.7 cm (50th centile) and weight was 21.2 kg (2nd centile) on Down syndrome-specific growth charts. She had suppressed thyroid-stimulating hormone (TSH) 0.01 mU/L (0.38–5.33) and elevated free T4 41.7 pmol/L (8.4–13.6) on annual screening bloods. TSH receptor (TSHR) antibodies were greater than 40 mU/L and thyroid peroxidase (TPO) antibodies were 146 mU/L consistent with GD. Carbimazole 15 mg daily in divided doses was commenced which brought TSH and free T4 into the normal range (shown in Fig. 1). With weaning, dose adjustments between 2.5 and 5 mg daily caused thyroid function to oscillate between mild biochemical hyperthyroidism and hypothyroidism.

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Thyroid Function and treatment over time.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 3; 10.1530/EDM-23-0064

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Twenty-eight months after diagnosis, her TSH was 15.5 mU/L and free T4 7.9 pmol/L and carbimazole was weaned to 5 mg daily. Two months later, repeat bloods demonstrated profound biochemical hypothyroidism (TSH: 257 mU/L, free T4: 3.2 pmol/L) and carbimazole was discontinued. Hypothyroidism persisted despite discontinuation (TSH: 182 mU/L, free T4: 5.1 pmol/L) and l-thyroxine 25 µg daily was commenced and titrated upward to 37.5 µg daily. Subsequent thyroid biochemistry suggested overtreatment which resulted in a progressive decrease in dosing and ultimately discontinuation 9 months after it was started. Hyperthyroidism (TSH: 0.01 mU/L and free T4: 18.1 pmol/L) persisted 3 months after discontinuation. At this point functional TSHR antibody bioassay was requested.

Investigation

Functional TSHR antibody bioassay demonstrated TBAb were positive at 79% (% inhibition <34) and TSAb were negative at 66% (% specimen-to-reference ratio <140) and thus the bioassay and thyroid biochemistry were discordant. Repeat bioassay 3 months later demonstrated that TBAb (71%) and TSAb (155%) were both positive and she remained mildly biochemically hyperthyroid at that point (TSH: 0.01 mU/L, free T4: 14.4 pmol/L).

Treatment

In line with existing literature, definitive treatment options needed consideration and accordingly, consultations were arranged regarding both radioactive iodine (RAI) and possible thyroidectomy. While waiting for consultations with radiation oncology and head-and-neck surgery and in discussion with the parents, a decision was made not to immediately recommence antithyroid drugs as it may trigger a further period of oscillating thyroid function and the biochemical abnormality was mild at that time. Thyroid function normalised off medication before both consultations could take place and a decision was taken at that point not to proceed with either definitive therapy at this time.

Block-and-replace therapy had been considered during the hyperthyroid phase; however, mild neutropaenia developed during carbimazole treatment. As neutropaenia from carbimazole is dose-related and higher carbimazole doses are necessary for block-and-replace therapy, we decided not to proceed with this option.

Outcome and follow-up

Since the initial diagnosis of GD, hyperthyroidism was treated with carbimazole for 2.5 years, followed by hypothyroidism treated with thyroxine for 9 months. Mild hyperthyroidism persisted off all treatment for 9 months and the subject is now euthyroid for the past 3 years. She does however remain at risk of relapse and will undergo regular thyroid function monitoring in accordance with national guidelines for Down syndrome medical surveillance.

Discussion

Metamorphic thyroid autoimmunity with switching between hypothyroidism and hyperthyroidism or vice versa is increasingly recognised (2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13). Less frequently reported, as in this case, are instances where the changes occur back and forth continuously over a period of time (11, 12, 13). In a recent study where TSAb and TBAb were quantified using a bioassay, less than 1% (10/1079) of the patients with autoimmune thyroid disease were positive for both (7). In a longitudinal study where patients were followed over 10 years (6), just 2/34 hypothyroid adults with TBAb predominance later developed TSAb-dominant hyperthyroidism. Similarly, just 2/98 adults with TSAb predominant GD later developed TBAb predominant hypothyroidism. Among non-switchers, hypothyroidism resolved in 87% of subjects in whom TBAb disappeared and GD went into remission in 82% of the subjects in whom TSAb disappeared (6). The predominant TSH receptor antibody subtype strongly correlates with thyroid status but as illustrated previously, the loss of TBAb or TSAb does not result in the resolution of hypothyroidism or GD in all cases (6). In one report, 10 patients who were positive for both TBAb and TSAb were either hypothyroid, euthyroid or hyperthyroid (7). We observed this in our case whereby biochemical hyperthyroidism was present on both occasions when a TSH receptor functional bioassay was undertaken; however, on the first occasion, the patient was positive for TBAb alone and 3 months later was positive for both TBAb and TSAb.

The mechanisms underpinning alternating thyroid status due to TSH receptor antibody switching have been reviewed in detail (14). These include changes in concentrations in TSAb compared to TBAb, their respective affinities and potencies, in addition to individual patient factors. Proposed mechanisms include antithyroid drug-related reduction in TSAb, l-thyroxine-mediated increase in TBAb in susceptible individuals (l-thyroxine is normally associated with a reduction in thyroid autoantibody levels) and hyperthyroidism-associated immune dysregulation caused by polarisation of antigen-presenting cells. Continued medical treatment can result in unremitting swinging between hypothyroidism and hyperthyroidism, leading most authors to advocate definitive treatment in the form of thyroidectomy or radioactive iodine. In discussion with the parents, we elected not to recommence carbimazole for mild biochemical hyperthyroidism in the months leading to what we initially presumed would be a definitive therapy; however, this was closely monitored. Based on our experience from the previous hyperthyroid phase, we felt that euthyroidism would likely not be achieved. No reliable data exists to guide what patients may go into remission; however, this report illustrates that it is another possible outcome for such patients. Since the initial diagnosis of GD, the subject reports that the most stable period of thyroid function has been achieved off all medical treatment and she has had a sustained period of euthyroidism off medication for 3 years. Despite the mechanisms proposed, alterations in the respective balance between TSAb and TBAb appear to also occur without medical treatment. In our report, TBAb alone and in combination with TSAb were identified at separate time intervals when neither carbimazole nor L-thyroxine were being administered. This observation is supported by data from a paper where six children with Down syndrome and HT, who after intervals of between 2.5 and 6.5 years, developed GD. Just three had received thyroxine treatment (2).

In some patients, this metamorphic thyroid autoimmunity is the result of the balance between TSAb and TBAb; however, this is unlikely the sole mechanism. In one series of patients with Down syndrome who progressed from HT to GD over time, all were TSH receptor antibody negative initially (4). Metamorphic thyroid autoimmunity in the paediatric population appears to be significantly more common in children with Down syndrome than the wider paediatric population (25% vs. 3.7%) (4). In one report, four children with Down syndrome and GD were reported to have developed hypothyroidism within a year of commencing antithyroid drugs and three were reported to alternate between hypothyroidism and hyperthyroidism (8). Detailed data regarding the clinical course or antibody phenotyping were not presented however. In a study by Aversa et al. (4), 12 patients with Down syndrome who initially had HT and were TSH receptor antibody negative later developed GD after varying intervals. Eight remained on antithyroid drugs and four went into remission and antithyroid drugs were discontinued. These four subsequently developed hypothyroidism within a short timeframe and commenced on and remained on thyroxine at the time of publication.

While metamorphic thyroid autoimmunity is common in Down syndrome, cases where thyroid function swings back and forth are particularly rare (8, 10). As medical treatment with antithyroid drugs or thyroxine are expected to cause alterations in the balance between TSAb and TBAb, definitive treatment has been advised. In our case, we elected not to recommence antithyroid drugs when mild hyperthyroidism persisted following discontinuation of thyroxine. Remission ensued and euthyroidism has persisted for 3 years off all treatment. In some reports of metamorphic thyroid autoimmunity from HT to GD, TSH receptor antibodies have been negative initially suggesting that switching between TBAb and TSAb was not the mechanism (4). Other reports have inferred the presence of both antibody subtypes but have not reported or demonstrated the same (8, 10). We demonstrated the presence of both TBAb and TSAb in this case and the fluctuating clinical course was consistent with this.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Patient consent

Written informed consent for publication of their clinical details was obtained from a parent of the patient.

Author contribution statement

MOG and GL were involved in the conception and design of the work, KF, AF and FS were involved in the acquisition and analysis of data. MOG wrote the preliminary manuscript draft, and it was revised and edited by KF, AF, FS and GL. All authors have seen the final manuscript draft and agree to be accountable for its contents.