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Thyroid
Resistance to Thyroid Hormone and Down Syndrome: Coincidental Association or Genetic Linkage? (doi: 10.1089/thy.2011-0316)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
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Resistance to Thyroid Hormone and Down Syndrome: Coincidental Association or
Genetic Linkage?
1. Fernández-García, JoséCarlos. MD.
2. López-Medina, JoséAntonio. MD, PhD.
3. Berchid-Debdi, Mohammed. MD.
4. Tinahones, Francisco José. MD, PhD.
All authors from:
Endocrinology Department, Hospital Virgen de la Victoria, Málaga, Spain.
Address for correspondence:
JoséCarlos Fernández-García: [email protected]
Servicio de Endocrinología y Nutrición, Hospital Virgen de la Victoria, Campus de
Teatinos s/n, 29010 Málaga, Spain.
Resistance to Thyroid Hormone and Down Syndrome
Key words: Resistance to thyroid hormone, Down syndrome, TRβ gene, goiter, genetic
linkage.
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Thyroid
Resistance to Thyroid Hormone and Down Syndrome: Coincidental Association or Genetic Linkage? (doi: 10.1089/thy.2011-0316)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
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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) and 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 a TSH of 10.7 µIU/mL and a 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 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 thyroidreleasing hormone (TRH) stimulation test; again, the TSH response was normal (See
Supplementary Data). Finally, a genetic study by PCR amplification of exons 3 to 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
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Thyroid
Resistance to Thyroid Hormone and Down Syndrome: Coincidental Association or Genetic Linkage? (doi: 10.1089/thy.2011-0316)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
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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 thyrotropin. 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
3
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Thyroid
Resistance to Thyroid Hormone and Down Syndrome: Coincidental Association or Genetic Linkage? (doi: 10.1089/thy.2011-0316)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
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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.
Disclosure statement: None of the authors has any relevant financial relationship with
any commercial interests.
References
1.
Konings CH, van Trotsenburg AS, Ris-Stalpers C, Vulsma T, Wiedijk BM, de
Vijlder JJ 2001 Plasma thyrotropin bioactivity in Down's syndrome children
with subclinical hypothyroidism. Eur J Endocrinol 144:1-4.
2.
Refetoff S, Weiss RE, Usala SJ 1993 The syndromes of resistance to thyroid
hormone. Endocr Rev 14:348-399.
3.
Reutrakul S, Sadow PM, Pannain S, Pohlenz J, Carvalho GA, Macchia PE,
Weiss RE, Refetoff S 2000 Search for abnormalities of nuclear corepressors,
coactivators, and a coregulator in families with resistance to thyroid hormone
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Thyroid
Resistance to Thyroid Hormone and Down Syndrome: Coincidental Association or Genetic Linkage? (doi: 10.1089/thy.2011-0316)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
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without mutations in thyroid hormone receptor beta or alpha genes. J Clin
Endocrinol Metab 85:3609-3617.
4.
Gene - National Center for Biotechnology Information (NCBI). Available at
www.ncbi.nlm.nih.gov/gene. Accessed December 7, 2011.
Table 1. Analytical evolution
TSH
Free T4
Free T3
(0.35-3.74 µIU/mL)
(0.76 -1.46 ng/dL)
(2.18-3.98 pg/mL)
Jun 2003
5.7
3.6
Not available
Jan 2004
10.7
3.5
Not available
Mar 2004
5.5
1.9
4.7
Oct 2004
5.8
2.3
4.8
Apr 2005
7.9
2.4
4.4
Oct 2005
9.6
3.2
4.2
Aug 2006
4.5
2.9
3.4
Apr 2007
8.6
2.3
3.5
Mar 2008
7.1
3.2
3.8
Oct 2008
6.7
3.4
3.3
Feb 2009
5.8
2.9
4.1
Sep 2009
8.4
3.3
3.9
Mar 2010
7.9
3.5
4.0
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Thyroid
Resistance to Thyroid Hormone and Down Syndrome: Coincidental Association or Genetic Linkage? (doi: 10.1089/thy.2011-0316)
This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
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Sep 2010
4.8
3.1
3.7
Mar 2011
5.3
3.3
4.2
Aug 2011
6.3
3.8
4.9
TSH: Thyroid-stimulating hormone
T4: Thyroxine
T3: Triiodothyronine
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