Resistance to Thyroid Hormone and Down Syndrome: Coincidental Association or Genetic Linkage?

Dear Editor:

We report the first association of resistance to thyroid hormone (RTH) and Down syndrome (DS).

A 3-year-old boy was referred to the Endocrinology Clinic for evaluation after detecting an alteration in his thyroid function results: thyroid-stimulating hormone (TSH), 5.7 μIU/mL (0.35–3.74); free thyroxine (fT4), 3.6 ng/dL (0.76–1.46). The patient had been diagnosed with DS (47, XY, +21) shortly after birth. On examination, his pulse was 78 bpm, the blood pressure was 110/74 mmHg, and his weight was 11.5 kg. Physical examination showed a DS phenotype, but no tremor. The psychomotor development was compatible with an age of 2–2.5 years. His bone age was in agreement with his age. Palpation showed a normal thyroid gland. No dermal myxedematous lesions or exophthalmos were noted. He was taking no medication. A repeat thyroid function test showed TSH of 10.7 μIU/mL and fT4 of 3.5 ng/dL. Antibodies against thyroid-stimulating immunoglobulin, thyroid peroxidase, and thyroglobulin were all negative. The alpha subunit of the TSH was 0.4 mU/mL (<0.9). The rest of the determinations were unremarkable. A thyroid ultrasound study showed a diffuse goiter with no evidence of nodules. A gadolinium-enhanced magnetic resonance study showed a normal pituitary. Given the clinical suspicion of RTH, the parents underwent a thyroid study, but the results were completely normal. The patient also underwent a thyroid-releasing hormone stimulation test; again, the TSH response was normal (see Supplementary Data, available online at www.liebertpub.com/thy). Finally, a genetic study by PCR amplification of exons 3–10 of the thyroid hormone β gene (TRβ) failed to detect any known mutation in the genes studied. Analytical follow-up of the patient has shown persistent elevated TSH levels despite increased fT4 and free triiodothyronine (fT3) concentrations (see Supplementary Data). However, the patient has remained completely asymptomatic and has required no treatment for management of the disease. Likewise, his growth is normal and his psychomotor development has been satisfactory.

First described by Refetoff in 1967, RTH is an unusual genetic disorder suspected analytically by high fT4 and fT3 concentrations together with non-suppressed levels of TSH. RTH is most often due to mutations in the gene coding for TRβ, located on chromosome 3, and it has an autosomal dominant mode of inheritance. Conversely, DS, resulting from the presence of an extra copy of human chromosome 21, is the most common genetic disorder in humans. DS is associated with a high prevalence of thyroid function disorders, mainly subclinical hypothyroidism. Indeed, given the high prevalence of mildly elevated TSH concentrations in DS, even in the absence of thyroid autoimmunity, it has been suggested that DS patients are less sensitive to thyroid hormone; however, TSH bioactivity has been shown to be normal (1).

Since the first description of RTH, over 120 different mutations in the TRβ gene have been reported. Most of these mutations, located between exon 4 and exon 10 and responsible for RTH in 85%–90% of cases, are missense mutations that induce substitutions in a single amino acid (2). Interestingly, in the present case no TRβ mutations were found. It has been reported that in 10%–15% of cases of RTH no mutations are discovered after DNA sequencing. These are known as non-TRβ-RTH mutations and are attributed to the presence of mutations related with the gene of one of the cofactors that interact with the receptor (3). After the diagnosis of non-TRβ RTH in our patient, we speculated about a possible relationship between RTH and DS chromosomal abnormalities and we looked for plausible genes on chromosome 21 whose dosage could be altered resulting in RTH. Thus, DS patients have a high prevalence of autoantibodies regarded as unique for autoimmune polyendocrine syndrome type 1, associated to autoimmune thyroid disease and caused by mutations in the AIRE gene on chromosome 21. However, most genes involved in thyroid regulation are located on chromosomes other than 21; indeed, only PTTG (a proto-oncogene implicated in the pathogenesis of thyroid tumors and in sodium iodide symporter expression) and PSMG1 (linked to papillary thyroid carcinoma) are found on chromosome 21 (4). Nevertheless, as new genes continuously come to light and new gene actions are found, this possibility cannot be ignored.

In summary, we report the first case of RTH and DS. Although this congruence could be coincidental, we cannot exclude a possible linkage between both syndromes. Further studies are warranted to elucidate the complex genetic variability of these entities and their possible associations with other genetic syndromes.