The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 8 2736-2738
Copyright © 1999 by The Endocrine Society
Concurrence of Pendred Syndrome, Autoimmune Thyroiditis, and Simple Goiter in One Family
Bijayeswar Vaidya,
Rebecca Coffey,
Beth Coyle,
Richard Trembath,
Camille San Lazaro,
William Reardon and
Pat Kendall-Taylor
Department of Medicine (Endocrinology) (B.V., P.K.-T.), University
of Newcastle upon Tyne, NE2 4HH, United Kingdom; Department of Clinical
Genetics and Fetal Medicine (R.C., W.R.), Institute of Child Health,
University of London, WC1N 1EH, United Kingdom; Department of Genetics
and Department of Medicine and Therapeutics (B.C., R.T.), University of
Leicester, LE1 7RH, United Kingdom; and Department of Paediatrics
(C.S.L.), Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP,
United Kingdom
Address all correspondence and requests for reprints to: Dr. B.Vaidya, Department of Medicine, 4th Floor Leech Building, The Medical School, University of Newcastle upon Tyne, NE2 4HH, United Kingdom. E-mail:
bvaidya{at}hgmp.mrc.ac.uk
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Abstract
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Pendred syndrome is the autosomal recessively transmitted association
of familial goiter and congenital deafness. There is no specific
biochemical marker of this disease, and the diagnosis depends upon the
demonstration of the triad of congenital sensorineural hearing loss,
goiter, and abnormal perchlorate discharge test. Pendred syndrome is
caused by mutations within the putative ion transporter gene (PDS
gene), located on chromosome 7q. A wide variation in the clinical
presentation of this condition, and its well documented phenotypic
overlap with other thyroid disorders (such as Hashimoto’s
thyroiditis), can lead to diagnostic difficulties. The potential for
misdiagnosis increases when these disorders occur coincidentally in the
same family. We describe a kindred in which Pendred syndrome,
autoimmune thyroiditis, and simple goiter coexisted, to highlight these
diagnostic pitfalls and to illustrate the use of mutational analysis in
resolving diagnostic confusion.
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Introduction
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PENDRED SYNDROME is the autosomal
recessively transmitted association of familial goiter and congenital
deafness (1). It is characterized by a partial defect of organification
of iodide into thyroglobulin in the thyroid gland and abnormal
discharge of unincorporated iodide on the administration of perchlorate
(2). Goiters in Pendred syndrome may be present at birth but typically
develop in late childhood and may vary significantly in size (3, 4).
Indeed, the overall prevalence of goiter in this condition remains
unsure, one recent paper identifying goiter in only 73% of familial
cases (5). Goiters tend to variably increase in size with time, often
despite the oral T4 therapy (5, 6). Pendred syndrome
is one of the most common forms of inherited childhood deafness and has
been estimated to be responsible for as much as 7.5% of all congenital
deafness (3). Deafness is sensorineural and usually evident at birth,
although it may not be recognized for several years. It is variably
associated with bilateral malformation of the cochlea (Mondini defect),
consisting of absence of the terminal half-coil of cochlea (7, 8), but
a much more frequent finding is dilated vestibular aqueduct (9).
Defective vestibular function is seen in about 66% of the cases (5).
The patients with Pendred syndrome are generally euthyroid, although
hypothyroidism can occur (6). The gene for Pendred syndrome (PDS gene)
was localized on chromosome 7q by genetic linkage studies (10, 11) and
was subsequently identified by positional cloning (12). The PDS gene
encodes a putative ion transporter, called Pendrin. Several common
mutations of this gene causing Pendred syndrome have recently been
identified, making molecular diagnosis of this condition possible
(12, 13, 14).
Although Pendred syndrome is a rare condition, with an estimated
incidence of 8 in 100,000 (3), other thyroid disorders with goiters,
such as simple goiter and autoimmune thyroiditis, are relatively common
in the population (15). Therefore, although rare, these disorders can
coexist in one family. The phenotypic overlaps between these disorders
are well known to cause diagnostic difficulties (16, 17, 18); however, the
potential for misdiagnosis further increases if these disorders occur
coincidentally in the same family, as we describe in this report. In
addition, we illustrate the application of mutational analysis in
resolving such diagnostic difficulties.
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Subjects and Methods
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Case reports
Two siblings (subjects III.2 and III.3, of the kindred shown in
Fig. 1
) have been deaf since birth.
Subject III.2 developed a smooth goiter at the age of 11 yr. Thyroid
function tests showed mild hypothyroidism, with a free T4
(FT4) level of 10.3 pmol/L (normal, 11.7–28) and TSH of
12.8 mU/L (normal, 0.25–4.3). She was started on T4
replacement. Her younger brother, subject III.3, developed a smooth
goiter at the age of 10 yr. At the age of 14 yr, when the goiter size
increased significantly and thyroid function tests showed an
FT4 level of 10.1 pmol/L and TSH of 4.8 mU/L, he was also
started on T4. Since diagnosis, goiter size has continued
to increase in both patients, and increasing doses of T4
have been necessary. Thyroid microsomal and thyroglobulin antibodies
were negative in both. Serum thyroglobulin measured in subject III.2
was within the normal range, at 29 mg/L (normal, 12–30). Karyotypic
analyses were normal (46XX and 46XY, respectively). Further
investigations in both siblings strongly supported an underlying
diagnosis of Pendred syndrome. Perchlorate discharge tests were
performed off oral T4 treatment; T4 was
substituted to T3, 8 weeks before the test, which
was stopped 2 weeks before the test. These tests were positive in both,
with 50% and 58% iodine discharge in subject III.2 and subject III.3,
respectively (normal, <10%). Pure-tone audiometry in both siblings
revealed bilaterally asymmetrical severe-to-profound sensorineural
deafness. Vestibular function, assessed with caloric testing and
electronystagmography, was normal in subject III.2 but showed a
decreased caloric response, on the left side, in subject III.3,
indicating impaired vestibular function. Computed tomograms
revealed bilateral malformation of the inner ear, typical of Pendred
syndrome, in both siblings. Both had dilated vestibular aqueducts
(subject III.2, 1.5 mm right and 2.7 mm left; subject III.3, 3.5 mm
bilaterally; normal, <1 mm), and subject III.3 additionally showed
deficiency of the interscalar septum on both sides, indicating a mild
Mondini malformation. Both siblings had normal growth and development
and have normal intelligence.
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Figure 1. Pedigree of the kindred, showing Pendred
syndrome, autoimmune thyroiditis, and simple goiter in one family. *,
Subjects not available for assessment.
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After the diagnosis of Pendred syndrome in the siblings, it was
found that their 15-yr-old elder sister (subject III.1) also had a
moderate-sized smooth diffuse goiter. She had no history of deafness,
and her audiogram was normal. Thyroid function test results were within
normal ranges, with an FT4 level of 14.7 pmol/L, and TSH of
3.9 mU/L. Thyroid autoantibodies were negative. However, in view of her
moderate-sized goiter, she was started on T4 (50
µg/daily). The absence of a hearing deficit, combined with normal
perchlorate discharge test results, made the diagnosis of Pendred
syndrome unlikely. Needle biopsy of the thyroid gland showed abundant
colloid with several sheets of thyroid epithelial cells, an appearance
suggestive of colloid goiter. There was no histological evidence of
Hashimoto’s thyroiditis. When she was reassessed, at the age of 22 yr,
it was noted that her goiter had regressed and thyroid autoantibodies
continued to be negative. She remained clinically and biochemically
euthyroid after stopping T4 for 8 weeks; therefore, it was
discontinued.
There was no history of deafness or thyroid disorder in the father
(subject II.2) of the propositi and his family line; however,
their mother (subject II.3) has been on T4 for many years.
She initially presented, at the age of 34 yr, with symptoms suggestive
of hypothyroidism, which was confirmed by thyroid function tests
showing an FT4 level of 9.3 pmol/L and TSH of 11.9 mU/L.
There was no palpable goiter, and she had normal hearing. Her
perchlorate discharge test was positive, with 20% iodine discharge.
However, she had thyroglobulin and microsomal autoantibodies (1:800 and
1:1600 titers, respectively), consistent with the diagnosis of
autoimmune thyroiditis. Her mother and one of her maternal aunts
(subjects I.7 and I.8) were also found to have been on T4
for antibody-positive hypothyroidism. They too had no goiter, and their
hearing was normal. Her three paternal aunts (subjects I.2, I.3, and
I.4) were known to have been deaf, although the exact etiology is
unknown, and were not available for investigation.
Segregation of the PDS gene mutation in the family
Methods. A donor splice site mutation, 1001 + 1G
A, in
exon 8 of the PDS gene has been identified in the siblings with Pendred
syndrome (subjects III.2 and III.3) (13). Segregation of the mutation
in the family was analyzed using the Fok I restriction
enzyme, whose site is gained in the presence of this mutation. PCR was
carried out, using previously referenced (13) PDS8 primers under
standard conditions for 35 cycles at 50 C, on a Peltier thermal cycler
(MJ Research, Inc., Watertown, MA). One hundred
nanograms of template DNA was amplified, using 37.5 ng of each primer,
in a 25-µL reaction, with 1.25 U Taq polymerase (PE Applied Biosystems, Epsom, UK) and 200 µmol
deoxynucleotide triphosphates. This was buffered with 100 mmol Tris-HCl
and 100 mmol KCl and 1 mmol MgCl2. Five microliters of
product was checked on a 1.5% Seakem LE agarose gel (FMC Bioproducts,
Lichfield, UK), before setting up digests on 15 µL of product
using 10 U Fok I (New England Biolabs, Inc.)
and 7 U HincII (Life Technologies, Paisley, UK) in 1x NEB4 buffer at 37 C for 3 h. Digested
products were then separated on a 4% Metaphor gel (FMC
BioProducts). The normal 211-bp band is digested into the bands
of 174 bp and 37 bp in the presence of the mutation (Fig. 2). All studies were carried out with the
approval of the ethics committee.
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Figure 2. Segregation of 1001 + 1GA mutation.
Mutation analysis was carried out in the affected sibs, elder sister,
and both parents, using FokI restriction enzyme. 1001 +
1GA mutation introduces an additional FokI site,
restricting the normal 211-bp fragment into bands of 174 bp and 37 bp
(too small to be resolved on agarose). The 408-bp PCR product is
normally cut into two bands of 211 bp and 197 bp by
FokI, which proved difficult to resolve. Hence,
HincII was included in the digests, because this cuts
the 197-bp band into two bands of 116 bp and 81 bp. The affected sibs
(subjects III.2 and III.3) are homozygous for the mutation, whereas
their elder sister (subject III.1) and both parents (subjects II.2 and
II.3) are heterozygous. M, Molecular size standard, which is the 1-kb
DNA ladder (Life Technologies).
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Results
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The affected sibs (subjects III.2 and III.3) were found to
be homozygous for the mutation, whereas their elder sister (subject
III.1) and both parents (subjects II.2 and II.3) were heterozygous
(Fig. 2
). These results support the clinical diagnosis of autoimmune
thyroiditis and simple goiter, rather than Pendred syndrome, in their
mother and elder sister, respectively.
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Discussion
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The diagnosis of Pendred syndrome is important because of
its implications, both for patient management and for genetic
counseling of the patients and their families. There is no specific
biochemical marker of the disease, and the diagnosis depends on the
demonstration of the triad of congenital perceptive hearing loss,
goiter, and abnormal perchlorate discharge test, although phenocopies
are well recognized (17, 18). Atypical cases of Pendred syndrome have
also been reported (16, 19, 20). Even within sibships, goiters vary
considerably in size and may even be absent (5). Similarly, the
deafness may be only partial or much more severe on one side than the
other. On the other hand, Hashimoto’s thyroiditis (goitrous autoimmune
thyroiditis) can mimic Pendred syndrome in clinical presentation,
especially if associated with hearing impairment. Hashimoto’s
thyroiditis, like Pendred syndrome, is known to occur in several
members of the same family (21). The perchlorate discharge test, which
is regarded as the hallmark of Pendred syndrome, can also be positive
in Hashimoto’s thyroiditis (17, 18, 22, 23), whereas false negative
results in Pendred syndrome have been reported (5). Furthermore,
thyroid autoantibodies can be present coincidentally in patients with
Pendred syndrome (6) and, very occasionally, be absent in Hashimoto’s
thyroiditis (24). The cochlear malformations, on computed tomography
scan and magnetic resonance imaging, are not specific to Pendred
syndrome but would not be expected to be present in Hashimoto’s
thyroiditis with or without hearing impairment. However, up to 10% of
Pendred syndrome cases have normal radiology of the cochlea (9). Hence,
radiological features cannot be relied on to differentiate between
these two eventualities. Similarly, differentiating sporadic goiter
from Pendred syndrome can also sometimes be difficult (16).
The absence of a single readily available diagnostic test for
Pendred syndrome, combined with the well-documented phenotypic overlap
with other thyroid disorders, can make for diagnostic difficulties. The
family that we present highlights these diagnostic pitfalls and
emphasizes the need for open-mindedness in approaching families with a
vague history of thyroid disease. Subject II.3 (Fig. 1) of our kindred
was diagnosed as having autoimmune thyroiditis, in spite of a positive
perchlorate discharge test, on the basis of the clinical presentation,
positive thyroid autoantibodies, and presence of autoimmune thyroiditis
in other family members. In subject III.1, Pendred syndrome and
Hashimoto’s disease were excluded, based on the clinical features,
normal perchlorate discharge test, negative thyroid autoantibodies, and
thyroid biopsy. Mutational analysis has helped to confirm and exclude
the diagnosis of Pendred syndrome in the family members. This family
demonstrates that the diagnosis of Pendred syndrome is firmly rooted in
on overall consideration of the clinical features, the family history,
and the interpretation of complex radiological and thyroid
investigations, relative to one another. With recent identification of
the common PDS gene mutations (12, 13, 14), the molecular diagnosis of
Pendred syndrome has become possible, which should ease the scope for
diagnostic confusion.
Received March 17, 1999.
Revised May 4, 1999.
Accepted May 10, 1999.
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Abstract
Introduction
