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CASE REPORT
GRAVES’ HYPERTHYROIDISM IN A PATIENT WITH PENDRED’S DYSHORMONOGENESIS
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IM Ibrahim
Endocrine Unit, Royal Victoria Infirmary, Newcastle upon Tyne, UK
DO McDonald
Institute of Human Genetics, Newcastle University, UK
Catherine J Owen
Institute of Human Genetics and School of Clinical Medical Sciences, Newcastle University, UK
, email:
c.j.owen@ncl.ac.uk
P Kendall-Taylor
Endocrine Unit, Royal Victoria Infirmary, Newcastle upon Tyne, UK and Institute of Human Genetics, Newcastle University, UK
Simon HS Pearce
Institute of Human Genetics and School of Clinical Medical Sciences, Newcastle University, UK
, email:
s.h.s.pearce@ncl.ac.uk
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Editorial 2009
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Reviewing Editor: Luca Persani
The authors have no conflict of interest related to this work.
Correspondence to:
Dr. Simon Pearce,
Institute of Human Genetics,
Newcastle University,
International Centre for Life, Central Parkway,
Newcastle upon Tyne, NE1 3BZ, UK.
Tel. 44-191-241-8674; Fax. 44-191-241-8666
ABSTRACT
The clinical details of a young woman with Pendred’s syndrome who developed autoimmune
hyperthyroidism are presented. Although the dyshormonogenesis of Pendred’s syndrome is
associated with a defect in iodide organification, her hyperthyroidism was successfully treated with 131-
I radioiodine. The nature of the thyroid hormonogenic defect in Pendred’s syndrome and the relative
functional importance of the apical iodide transporting mechanisms are illustrated. In addition, the
hyperthyroidism, and its subsequent treatment, clearly demonstrate that Pendred’s syndrome results
only from a partial block to thyroid hormone synthesis. Radioiodine, perhaps administered after
recombinant TSH thyroid stimulation, may be an alternative treatment for goitre in Pendred’s
syndrome. (Hot Thyroidol. 2009: e13).
Introduction
Pendred’s syndrome (PDS) is an autosomal recessive disorder characterized by congenital
sensorineural hearing loss and progressive goitre (1). Other features of PDS are enlargement of the
vestibular aqueduct and “Mondini” malformation of the cochlea, which are typically present on
imaging studies. In about 50% of patients, the circulating thyroid hormone levels are normal, while the
remainder develop overt hypothyroidism due to defective iodide transport, which results in thyroid
dyshormonogenesis (2). Typically, affected subjects demonstrate avid thyroidal iodide uptake but
impaired iodide organification, as determined by an exaggerated release of uncoupled radioiodine
tracer from the thyroid following perchlorate administration (a positive perchlorate discharge test) (3).
PDS was assigned to chromosome 7q31 by linkage analysis (4,5), and mutations in the gene
encoding an anion transporter, SLC26A4, also termed “Pendrin” were found in affected patients (6).
There are now more than 50 such independent SLC26A4 gene mutations that have been
characterized as causing PDS (6-12). The mature SLC26A4 transporter is located on the apical
membrane of thyrocyte (13,14), where it is responsible for the transport of inorganic iodide into the
colloid space. Iodide is then available for organification and subsequent incorporation into
iodotyrosine compounds, the precursors of thyroid hormones. Pendrin acts as an anion exchanger,
allowing iodide flux out of the thyrocyte with a reciprocal influx of chloride. In the presence of a loss of
function in the SLC26A4 transporter, apical iodide transport is defective, leading to impaired
organification of iodide and the hypothyroidism of Pendred’s syndrome. However, as many patients
with PDS remain euthyroid, organification is only partially deficient, suggesting that there may be
either functional heterogeneity in the activity of the abnormal transporters in PDS or that other
mechanisms exist that can compensate for lack of the SLC26A4 protein activity (15). In this paper we
report a rare association of autoimmune hyperthyroidism in a patient with PDS, and its treatment.
Case report
The patient is the daughter of unrelated parents who were both known to have Pendred’s syndrome
(PDS). There was no family history of autoimmune disorders. At the age of 2 years, she was found to
have sensorineural deafness and clinical examination showed her to have a large goitre. Because of
her family background, she was thought likely to be an obligate carrier of two SLC26A4 gene
mutations, and compound heterozygosity for a 1101+1G>A and 2015G>A base changes within the
SLC26A4 gene were demonstrated (9). These DNA changes predict a donor splice-site mutation of
exon 8 and a non-conservative G672E missense mutation in exon 17 of SLC26A4, respectively. Both
mutations are likely to result in a non-functional protein, encoding a transporter either with a missing
domain, or one that is unable to reach the cell surface due to misfolding, respectively (16).
At the age of eleven years, she was first found to be biochemically hypothyroid with a serum TSH of
6.4mU/l; she was treated with thyroxine 150μg daily, with the aim to keep the serum TSH towards the
lower limit of normal to suppress the growth of her goitre. She attended clinic sporadically, when her mother and a sign-language interpreter were available to accompany her. However, at the age of 18
she lost 17 Kg in weight, associated with tremor, heat intolerance and palpitations. There were no eye
signs or thyroid dermopathy. Her repeat thyroid function tests showed a raised free T4 of 64 pmol/l
(normal range 11-23), free T3 of 13.7 pmol/l (3.5-6.5), and an undetectable TSH. Thyrotropin-binding
inhibitory immunoglobulins (TBII) were raised at 36 U (normal <10) and thyroid peroxidase antibodies
were positive at 89 kU/l (normal <60). Her serum thyroglobulin measured by RIA was 63.4 μg/l. Full
details of the course of her thyroid function tests are shown in Table 1. A 99m-Tc thyroid uptake scan
showed a patchy but widespread increase in uptake (Figure 1).
Figure 1. 99m-Tc (pertechnetate) thyroid uptake scan. The 20 minute thyroid uptake was 10% of tracer (normal <3.5%).
After repeat testing, her thyroxine medication was stopped, but she remained mildly hyperthyroid
despite this. After some discussion about the uncertain outcome, she agreed to radioiodine as
therapy for her hyperthyroidism and was treated with 400MBq (11mCi) 131-I. Her thyroid function tests
became normal 7 weeks after the treatment and she was restarted on thyroxine and remains well at
last follow up (Table 1). There was substantial reduction in her goitre noted over the 6 months
following her radioiodine therapy.
Table 1. Thyroid function testing and weight
Methods
Mutational analysis.
The genetic analysis of this patient (III-1) and her family have been previously reported, with her
paternal and maternal relatives being designated as families 14 and 13, respectively (9).
Biochemical assays.
Serum thyrotropin (TSH) was analyzed using the Bayer ADVIA Centaur analyzer (Bayer Diagnostics
Division, Newbury Berkshire, UK) by 2 site sandwich immunoassay using direct chemiluminescence.
Serum free T4, free T3 and anti-thyroid peroxidase antibodies were measured by competitive
immunoassay using direct chemiluminescent technology (Bayer centaur). Thyrotropin-binding
inhibitory immunoglobulins (TBII) assay (RSR Ltd, Pentwyn,Cardiff, UK), measure the ability of TBII in
the patient sample to inhibit the binding of 125I-Labelled TSH to recombinant thyroid receptors on
coated polystyrene tubes. The % inhibition is calculated as an index.
Thyroglobulin (Tg) was measured using coated tube 2 site immunoradiometric sandwich assay, using
4 monoclonal anti (Tg) antibodies to specific sites on (Tg) molecule on coated tubes (CIS Bio
international). The intra-assay coefficients of variation for each measurement (at the given
concentration) were: TSH 3.8% (5.3mU/l), FT4 7.9% (13.5pmol/l), FT3 6.3% (4.5pmol/l), thyroid
peroxidase antibodies 3.7% (522kU/l), TBII 8% (37U), Tg 8.4% (17μg/l).
Discussion
Our investigations show that this young woman who had Pendred’s syndrome, a state of thyroid
dyshormonogenesis, developed hyperthyroidism owing to Graves’ disease. Although at first, the
diagnosis of thyrotoxicosis ‘factitia’ due to excessive thyroxine ingestion was suspected, several
factors suggested true autoimmune hyperthyroidism as the cause of the thyrotoxicosis. These include
a progressive rise in circulating thyroid hormone levels during treatment with a stable dose of Lthyroxine,
detectable serum thyroglobulin at the time of thyrotoxicosis, positive thyroid peroxidase and
thyrotropin-binding inhibitory autoantibodies, and a low serum thyroxine to triiodothyronine ratio once
thyroxine was discontinued. Her thyroid uptake scan is particularly difficult to interpret, since a rapid
uptake of pertechnetate tracer has been reported in untreated Pendred’s syndrome, probably driven
by a high-normal or high TSH. However, in the context of an undetectable TSH, the high
pertechnetate uptake (10% at 20 mins; normal <3.5%) is caused, at least in part, by her endogenous
hyperthyroidism due to thyroid stimulation with TSH-receptor antibodies (Figure 1). In a person with
no underlying thyroid disease, low isotope uptake would be expected in the presence of an
undetectable TSH during exogenous thyroxine administration. The improvement in thyrotoxicosis
following the radioiodine and the subsequent reduction in goitre size are also in keeping with the
diagnosis of Graves’ disease.
Radioiodine was selected as treatment for this patient because she was keen to avoid thyroid
surgery, which both her mother and her maternal uncle (who was also affected with PDS) had
undergone, and there was the additional possibility of shrinkage of her goitre with the treatment. We
were unsure whether radioiodine would be efficacious in this circumstance: there are no previous
reports of radioiodine use in PDS. Nevertheless, as we were confident she had endogenous
hyperthyroidism, it was clear she could trap and organify enough iodide to become thyrotoxic.
Therefore, it seemed reasonable to assume there would be a therapeutic effect from radioiodine.
Since she had a reduction in goitre size with the radioiodine, it is possible that this may be a useful
therapeutic option for goitre reduction in other patients with PDS, perhaps administered following
recombinant TSH stimulation, rather than with the endogenous TSH-receptor stimulation from
autoantibodies as in this case. This is an area of practice where there is little published experience.
Thyroid autoantibodies, including TSH receptor stimulating antibodies, have been previously reported
in Pendred’s syndrome (17), which suggests that there may be a predisposition to thyroid
autoimmunity in PDS patients. The large size of the thyroid gland in PDS, together with increased
expression or turnover of the proteins involved in thyroid hormone biosynthesis, which are also the
targets of the autoimmune attack, could explain an association of thyroid autoimmunity and this form
of dyshormonogenesis. In particular, there is evidence of upregulation of thyroid peroxidase activity in
PDS thyroid tissue (18, 19). Although, one study has shown genetic linkage of a large family with
autoimmune thyroid disease to the chromosomal interval containing the PDS locus (20), there is
currently no formal evidence to support the idea that genomic variation in the SLC26A4 gene itself is responsible for autoimmunity. Interestingly, autoantibodies recognizing Pendrin protein have recently
been described in Hashimoto’s thyroiditis and, to a lesser extent in Graves’ disease, using
immunoblotting with patient sera (21).
During thyroid hormone synthesis, the initial transport of iodide from the circulation (extracellular fluid)
occurs at the basolateral surface of the thyrocyte through the sodium-iodide symporter (NIS). This
has the ability to transport iodide up a 20-fold concentration gradient to allow its accumulation in the
thyrocyte. Inorganic iodide is then transported across the apical membrane of the thyrocyte, to bring it
into close proximity to thyroid peroxidase, which is anchored to the apical membrane but with its
catalytic “head” in the colloid space. Iodide crossing the apical membrane via SLC26A4 is available to
TPO to organify, whence it is rapidly incorporated into the tyrosyl residues of thyroglobulin to form the
iodotyrosine thyroid hormone precursor molecules. Thus, one might predict that it would be difficult or
impossible for an individual with the defective apical iodide transport found in PDS to become
hyperthyroid. However, it is clear from our clinical findings in this case, that under certain conditions
SLC26A4-mediated iodide transport is not a significantly rate-limiting step in thyroid-hormone
synthesis. Since many patients with PDS remain euthyroid for many years, iodide organification is
only partially deficient in many individuals with this condition, suggesting that other mechanisms of
iodine transport exist that can compensate for lack of the SLC26A4 protein (15). Some studies (22,
23) have suggested that iodide efflux can also be mediated through a TSH-induced iodide porter via
either a cAMP or a Ca2+ PIP2
pathway. Golstein et al., (24) used a membrane vesicle preparation of
bovine thyroid to characterize two iodide channels with distinct biophysical properties. A second
iodide transport mechanism has recently been proposed, termed the human apical iodide transporter
( hAIT or SLC5A8), with substantial structural homology to the basolateral NIS co-transporter, but with
an apical distribution in thyrocytes (25). This report goes someway to confirming the physiological
relevance of an additional apical iodide channel(s) in man, that can compensate for defective
transport mediated by SLC26A4.
To summarize, we report the probably unique case of a young woman with PDS who developed
hyperthyroidism owing to Graves’ disease. The clinical findings are used to illustrate the normal
physiology of thyroid hormone synthesis, the mechanisms of apical iodide transport in the thyrocyte
and the pathophysiology of dyhormonogenesis. The patient was successfully treated with a
conventional dose of radioiodine, and this treatment may be worthy of further investigation in this
condition.
Acknowledgements
We are grateful to Prof. R. Trembath, King’s College London, for collaboration in the genetic studies,
to Mr. Steve Turner of the Biochemistry Dept. Newcastle upon Tyne NHS Hospital trust for assistance
with clinical chemistry and to Drs. Tim Cheetham and John Pearce for helpful comments about the
manuscript.
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Address:
CASE REPORT
GRAVES’ HYPERTHYROIDISM IN A PATIENT WITH PENDRED’S DYSHORMONOGENESIS |
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Title: Hot Thyroidology; Abbreviated key title: Hot Thyroidol.; Online ISSN: 2075-2202
Legal Note: © All rights reserved European Thyroid Association 2009
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