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A Child with Non-Autoimmune Hyperthyroidism

Last Updated: · Doctors


Dear Experts,

I was recently asked for a second opinion about a child now aged 10yrs 7 mos who has non-autoimmune hyperthyroidism first diagnosed at 3 yrs age following investigation for tachycardia. Her initial FT4 was 77pmol/l and her TSH was <0.03mU/l. As far as I am aware, FT3 was not formed. All thyroid antibodies were and are negative. The issue I was asked to discuss was whether radioactive iodine was safe in children as definitive treatment for her condition, because the physicians primarily involved in her treatment would like to discontinue PTU. That is not my question to you.

Salient features of this child include: 1) She has some subtle dysmorphism, namely a marfanoid body habitus with high arched palate, narrow face, arachnodactyly, mild thoracic kyphosis. 2) She has mitral valve prolapse 3) she has hypoplastic cochleas on CT with low frequency hearing loss. 4) She is said to have some mild developmental delay. 5) she has a hyperfunctioning nodular goitre 6) She has been managed on PTU at a fairly low dose for several years. This has resulted in FT4 levels in the low or low-normal range (around 6-12pmol/l) and FT3 levels in the high-normal to high range (similarly,around 6-12 pmol/l). Her TSH has remained super-suppressed apart from a recent result (TSH 0.14mU/l, FT4 6.4pmol/l (low), FT3 6.3pmol/l (normal)).

Her clinical findings however are mixed: significant growth failure over the past 4 yrs (97th to 25th percentlies), a history of persistent tachycardia investigated by her cardiologist and evident when I examined her, dry coarse hair, normal reflexes. Her growth failure may be catch-down because her mid-parental height is on the 25th percentile. A bone age obtained a couple of yrs ago was a months advanced compared with her chronological age.

7) Reportedly, her mother and brother have normal thyroid function tests, her father has not been tested. The paternal grandmother developed hypothyroidism late in life.

I am reasonably confident that she has a molecular defect responsible for her hyperthyroidism. I think that this is most likely an activating mutation of the TSH receptor however the following things bother me: 1) Cochlea abnormalities and/or deafness have not been reported in association activating mutations of the TSH receptor (as far as I can tell) but have been reported in association with TRbeta mutations. TRbeta mutations are also associated with a mixed picture of hyper and hypothyroid features, specifically the co-existance of persistent tachycardia and growth failure; however unless I am missing something, her TSH concentration excludes a TRbeta mutation. Am I missing something? 2) MV prolapse would be consistent with an activating mutation of the TSH receptor. Would local activation of TSH receptors in the heart explain the persistent tachycardia? Are there any data on what happens to children (or indeed adults) with germline activating mutations of the TSH receptor post ablation with respect to persistence of symptoms during thyroxine replacement therapy? I have only found 1 case report that addresses long term follow up. From the point of view of her supposed hypothyroid signs, even if the plasma FT3 concentration is not a reflection of intracellular or nuclear T3, I cannot see why intracellular T3 would be low; therefore I do not understand the basis of her hypothyroid features, namely dry coarse hair and (if it is due to hypothyroidism) growth failure

I would appreciate any thoughts you may have on this child. I have advised the parents that although radioactive iodine in appropriate doses would be safe, I think it would be advisable to understand better the underlying mechanism of her thyroid disease beforehand. In the meantime, I have suggested trying to fully suppress thyroid function with a bigger dose of PTU and replacing her with thyroxine to mimic (more or less) what would happen post-ablation when she is on Thyroxine alone. The family are very willing to donate DNA for molecular analysis. I therefore would also appreciate advice on who might be interested in looking at what. I look forward to your response(s).

Jan Walker MBBS FRACP, Head, Endocrinology, Sydney Children's Hospital


It is possible that she has an activating mutation in the TSH receptor (TSHR) but, without evidence of inheritance, which should be dominant, I cannot be as confident as you suggest. The absence of antibodies or other stigmata, such as ophthalmopathy and dermopathy, cannot exclude autoimmune thyroid disease (AITD) as the etiology of the thyrotoxicosis. She could be the product of a de-novo germline mutation. The only way to be sure is to sequence her TSHR, which is not difficult, in our day and age, to accomplish. I would be interested to know what you mean exactly by "hyperfunctioning nodular goiter"? Is the gland irregular but diffusely hyperfunctioning or is the increased radioiodide uptake confined to several nodules. Multiple somatic gain-of-function mutations have been reported, though not in children. Resistance to thyroid hormone (RTH) due to a mutation in the thyroid hormone receptor (TR) beta gene is less likely for the reason you have stated below, namely suppressed TSH. This condition is also inherited as a dominant trait and, taking into account the prevalence of de-novo mutations, the chances are 85% that one of her parents should be also affected. As far as I know TSHR is not expressed in the heart, and if it were, it is unclear to me how it will affect the heart by stimulating cAMP. Rather, the high thyroid hormone levels (mainly T3 in this case) is the likely reason for tachycardia. Incidentally, tissues that are more dependent of intracellular generation of T3 from T4, could be relatively hypothyroid. Human skin fibroblast have abundant type 2 5'-deiodinase. Thus, the apparent T3-toxicosis may be the reason for some of the discrepant findings. Furthermore, neonatal thyrotoxicosis can produce a prolonged suppression of TSH (in man and in rat) presumably through its suppressive effect on the hypothalamus. Such individuals, and animals, can present prolonged post thyrotoxic central hypothyroidism. Individuals with activating mutations are particularly resistant to antithyroid drugs and thyrotoxicosis has the tendency to recur after surgical ablation due to the persistent constitutive activation of the thyroid remnant. Thus, these patients are good candidates for radioiodide treatment, even at young age. Although this was not your question, I fully agree with your statement that confirmation of gain-of-function TSHR mutation before administering this form of treatment. Regarding the somatic abnormalities, these may indicate that the genetic defect may be more extensive than just a point mutation in the TSHR. Have you done chromosomal analysis, either banding or by the newer spectral karyotyping technique?

Samuel Refetoff, M.D.